PSEN1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007219 Notch signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: PSEN1 is the catalytic presenilin subunit of gamma-secretase, which cleaves Notch receptors. The conserved PAINT annotation to Notch signaling is appropriate because Notch receptor processing is a core evolved function of presenilin/gamma-secretase biology. Reason: Gamma-secretase cleaves Notch receptor substrates, and PSEN1 is the catalytic presenilin component of the complex. This is a core function, not only an Alzheimer disease context. Supporting Evidence: PMID:15274632 This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving	IBA GO_REF:0000033	ACCEPT	Summary: PSEN1 provides the catalytic aspartate protease activity of the gamma-secretase intramembrane protease complex. This molecular-function annotation is central and should be retained. Reason: Structural and biochemical work places the PSEN1 catalytic aspartates in the membrane-embedded active site of human gamma-secretase. Supporting Evidence: PMID:26280335 Among the two catalytic residues, Asp257 is located in the middle of TM6 slightly to the extracellular side, whereas Asp385 maps to the cytoplasmic side of TM7
GO:0055074 calcium ion homeostasis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Presenilin proteins have experimental support for ER calcium leak channel activity independent of gamma-secretase, but this is a secondary function relative to PSEN1's core gamma-secretase protease role. Reason: The annotation is biologically plausible and supported, but calcium homeostasis is best treated as a non-core presenilin activity for this review until the in-vivo physiological scope is separated from disease and cell-culture contexts. Supporting Evidence: PMID:16959576 presenilins account for approximately 80% of passive Ca(2+) leak from the endoplasmic reticulum.
GO:0016485 protein processing	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: PSEN1 participates in proteolytic processing of membrane proteins as the catalytic presenilin subunit of gamma-secretase. The term is broad, but the PAINT annotation captures a real core process. Reason: The annotation is correct but less informative than the more specific membrane-protein ectodomain/intramembrane proteolysis and amyloid-beta/Notch processing annotations; retain as non-core broad process context. Supporting Evidence: PMID:15274632 yeast cells suggest that PS, NCT, Aph-1, and Pen-2 are necessary and sufficient to reconstitute gamma-secretase activity.
GO:0006509 membrane protein ectodomain proteolysis	IBA GO_REF:0000033	ACCEPT	Summary: PSEN1/gamma-secretase cleaves type I membrane-protein substrates after ectodomain shedding, including APP and Notch receptor fragments. This is a core process annotation. Reason: The annotation reflects PSEN1's conserved role in gamma-secretase substrate processing of membrane proteins. Supporting Evidence: PMID:15274632 Gamma-secretase is a member of an unusual class of proteases with intramembrane catalytic sites.
GO:0034205 amyloid-beta formation	IBA GO_REF:0000033	ACCEPT	Summary: PSEN1-containing gamma-secretase cleaves APP-derived C-terminal fragments and generates amyloid-beta peptides. This is a core substrate processing outcome of PSEN1 gamma-secretase activity. Reason: Purified gamma-secretase and structural studies support PSEN1 as the catalytic subunit responsible for APP cleavage leading to amyloid-beta production. Supporting Evidence: PMID:26280335 Among these components, presenilin is responsible for the Aβ-producing proteolytic activity7,8.
GO:0070765 gamma-secretase complex	IBA GO_REF:0000033	ACCEPT	Summary: PSEN1 is a core component of the mature gamma-secretase complex, present as N- and C-terminal fragments with nicastrin, APH1, and PEN2. Reason: This cellular-component annotation directly represents the complex in which PSEN1 performs its core catalytic role. Supporting Evidence: PMID:15274632 Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
GO:0000139 Golgi membrane	IEA GO_REF:0000044	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0000776 kinetochore	IEA GO_REF:0000117	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0005769 early endosome	IEA GO_REF:0000120	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0007220 Notch receptor processing	IEA GO_REF:0000117	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0016020 membrane	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0016485 protein processing	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage. Reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis terms carry the core functional information.
GO:0030424 axon	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0030426 growth cone	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0031901 early endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0031965 nuclear membrane	IEA GO_REF:0000117	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0035556 intracellular signal transduction	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving	IEA GO_REF:0000120	ACCEPT	Summary: PSEN1 is the catalytic presenilin subunit of gamma-secretase, a membrane-embedded aspartyl protease complex that cleaves type I membrane-protein substrates including APP and Notch. Reason: This annotation reflects the core evolved function of PSEN1 in regulated intramembrane proteolysis. Structural and biochemical evidence identify presenilin as the catalytic component of mature gamma-secretase.
GO:0042987 amyloid precursor protein catabolic process	IEA GO_REF:0000002	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0043005 neuron projection	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0045202 synapse	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0070588 calcium ion transmembrane transport	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase, but this is secondary to the core gamma-secretase role. Reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity, but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
GO:0098794 postsynapse	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0005515 protein binding	IPI PMID:11083918 X11 alpha and x11 beta interact with presenilin-1 via their ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:12901838 Presenilin-1 interacts directly with the beta-site amyloid p...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:15322109 Both the sequence and length of the C terminus of PEN-2 are ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:16007100 Autoinhibition of X11/Mint scaffold proteins revealed by the...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:16641999 TMP21 is a presenilin complex component that modulates gamma...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:18201567 Cellular localization of Nicastrin affects amyloid beta spec...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:21115843 Activation and intrinsic gamma-secretase activity of preseni...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:21163940 Interactome mapping suggests new mechanistic details underly...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:25394380 G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Inc...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:26280335 An atomic structure of human γ-secretase.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:29611543 Intracellular trafficking of TREM2 is regulated by presenili...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:30559186 Bax inhibitor 1 is a γ-secretase-independent presenilin-bind...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:9223340 Interaction between amyloid precursor protein and presenilin...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0001921 positive regulation of receptor recycling	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0003407 neural retina development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0004175 endopeptidase activity	IEA GO_REF:0000120	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0004190 aspartic-type endopeptidase activity	IEA GO_REF:0000107	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0005634 nucleus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0005737 cytoplasm	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0005765 lysosomal membrane	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0005794 Golgi apparatus	IEA GO_REF:0000107	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005938 cell cortex	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0006509 membrane protein ectodomain proteolysis	IEA GO_REF:0000120	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0008021 synaptic vesicle	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0008233 peptidase activity	IEA GO_REF:0000107	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0009986 cell surface	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0021549 cerebellum development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0030425 dendrite	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0031594 neuromuscular junction	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0032991 protein-containing complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0035253 ciliary rootlet	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0042383 sarcolemma	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0042734 presynaptic membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0043198 dendritic shaft	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0043524 negative regulation of neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0043589 skin morphogenesis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site	IEA GO_REF:0000107	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0045296 cadherin binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Specific cadherin binding annotation for PSEN1-associated complexes or interactors. Reason: The interaction is biologically relevant but secondary to the core gamma-secretase catalytic role; retain as non-core interaction context.
GO:0060828 regulation of canonical Wnt signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0070765 gamma-secretase complex	IEA GO_REF:0000107	ACCEPT	Summary: PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and PEN2. Reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other gamma-secretase subunits for mature protease activity.
GO:0097060 synaptic membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0098693 regulation of synaptic vesicle cycle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0099175 regulation of postsynapse organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0140249 protein catabolic process at postsynapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:2000059 negative regulation of ubiquitin-dependent protein catabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0005794 Golgi apparatus	IDA GO_REF:0000052	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0000139 Golgi membrane	EXP PMID:10593990 Cell surface presenilin-1 participates in the gamma-secretas...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0000139 Golgi membrane	EXP PMID:8574969 Alzheimer-associated presenilins 1 and 2: neuronal expressio...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005769 early endosome	EXP PMID:25394380 G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Inc...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005783 endoplasmic reticulum	EXP PMID:25394380 G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Inc...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:10593990 Cell surface presenilin-1 participates in the gamma-secretas...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:8574969 Alzheimer-associated presenilins 1 and 2: neuronal expressio...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:9738936 Direct association of presenilin-1 with beta-catenin.	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	EXP PMID:10593990 Cell surface presenilin-1 participates in the gamma-secretas...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	EXP PMID:11953314 A presenilin-1/gamma-secretase cleavage releases the E-cadhe...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	EXP PMID:11987239 Identification of the presenilins in hematopoietic cells wit...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0045202 synapse	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0035556 intracellular signal transduction	IMP PMID:10508860 Presenilin 1 suppresses the function of c-Jun homodimers via...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0060090 molecular adaptor activity	IDA PMID:9689133 Presenilin 1 associates with glycogen synthase kinase-3beta ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0007611 learning or memory	IGI PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cell...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0030425 dendrite	IDA PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzhei...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0010629 negative regulation of gene expression	IGI PMID:28008308 The Protective Role of microRNA-200c in Alzheimer's Disease ...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0007611 learning or memory	IGI PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzhei...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0007611 learning or memory	IGI PMID:24052308 Human LilrB2 is a β-amyloid receptor and its murine homolog ...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0007613 memory	IGI PMID:11880515 The relationship between Abeta and memory in the Tg2576 mous...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0010628 positive regulation of gene expression	IGI PMID:28008308 The Protective Role of microRNA-200c in Alzheimer's Disease ...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0050808 synapse organization	IGI PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzhei...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0004175 endopeptidase activity	IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ...	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0004175 endopeptidase activity	IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se...	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0005515 protein binding	IPI PMID:12522139 PEN-2 and APH-1 coordinately regulate proteolytic processing...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0007220 Notch receptor processing	IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0016485 protein processing	IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ...	KEEP AS NON CORE	Summary: Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage. Reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis terms carry the core functional information.
GO:0016485 protein processing	IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se...	KEEP AS NON CORE	Summary: Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage. Reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis terms carry the core functional information.
GO:0016485 protein processing	IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su...	KEEP AS NON CORE	Summary: Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage. Reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis terms carry the core functional information.
GO:0034205 amyloid-beta formation	IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0034205 amyloid-beta formation	IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0034205 amyloid-beta formation	IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0042987 amyloid precursor protein catabolic process	IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0042987 amyloid precursor protein catabolic process	IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0042987 amyloid precursor protein catabolic process	IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0070765 gamma-secretase complex	IDA PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ...	ACCEPT	Summary: PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and PEN2. Reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other gamma-secretase subunits for mature protease activity.
GO:0070765 gamma-secretase complex	IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se...	ACCEPT	Summary: PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and PEN2. Reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other gamma-secretase subunits for mature protease activity.
GO:0006974 DNA damage response	IDA PMID:25542424 The miR-193a-3p regulated PSEN1 gene suppresses the multi-ch...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0005515 protein binding	IPI PMID:26094765 Proton myo-inositol cotransporter is a novel γ-secretase ass...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0051117 ATPase binding	IPI PMID:26094765 Proton myo-inositol cotransporter is a novel γ-secretase ass...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0070851 growth factor receptor binding	IPI PMID:26094765 Proton myo-inositol cotransporter is a novel γ-secretase ass...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0010468 regulation of gene expression	IGI PMID:26200696 Dual pathways mediate β-amyloid stimulated glutathione relea...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0010628 positive regulation of gene expression	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0010629 negative regulation of gene expression	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0032760 positive regulation of tumor necrosis factor production	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0045821 positive regulation of glycolytic process	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0032469 endoplasmic reticulum calcium ion homeostasis	IMP PMID:25394380 G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Inc...	KEEP AS NON CORE	Summary: Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase, but this is secondary to the core gamma-secretase role. Reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity, but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
GO:0010975 regulation of neuron projection development	IMP PMID:15004326 A novel highly pathogenic Alzheimer presenilin-1 mutation in...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0030426 growth cone	IDA PMID:15004326 A novel highly pathogenic Alzheimer presenilin-1 mutation in...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0043005 neuron projection	IDA PMID:15004326 A novel highly pathogenic Alzheimer presenilin-1 mutation in...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving	IMP PMID:17428795 Ligand binding and calcium influx induce distinct ectodomain...	ACCEPT	Summary: PSEN1 is the catalytic presenilin subunit of gamma-secretase, a membrane-embedded aspartyl protease complex that cleaves type I membrane-protein substrates including APP and Notch. Reason: This annotation reflects the core evolved function of PSEN1 in regulated intramembrane proteolysis. Structural and biochemical evidence identify presenilin as the catalytic component of mature gamma-secretase.
GO:1990535 neuron projection maintenance	IGI PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cell...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0098609 cell-cell adhesion	IMP PMID:11953314 A presenilin-1/gamma-secretase cleavage releases the E-cadhe...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-1251997	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-193682	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-205112	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-2220988	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-3928656	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798739	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9013361	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9017817	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9839376	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-NUL-2197556	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	TAS Reactome:R-NUL-9604300	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:1905908 positive regulation of amyloid fibril formation	IGI PMID:11880515 The relationship between Abeta and memory in the Tg2576 mous...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1. Proposed replacements: amyloid-beta formation
GO:0004190 aspartic-type endopeptidase activity	NAS PMID:24217950 Ligand-dependent activation of EphA4 signaling regulates the...	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0048143 astrocyte activation	IGI PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cell...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0002265 astrocyte activation involved in immune response	IGI PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local cl...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:1904646 cellular response to amyloid-beta	IGI PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local cl...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1. Proposed replacements: amyloid-beta formation
GO:0005515 protein binding	IPI PMID:10508860 Presenilin 1 suppresses the function of c-Jun homodimers via...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005634 nucleus	IMP PMID:10508860 Presenilin 1 suppresses the function of c-Jun homodimers via...	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0005790 smooth endoplasmic reticulum	IDA PMID:10508860 Presenilin 1 suppresses the function of c-Jun homodimers via...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0032991 protein-containing complex	IMP PMID:10508860 Presenilin 1 suppresses the function of c-Jun homodimers via...	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0016020 membrane	IDA PMID:26280335 An atomic structure of human γ-secretase.	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0034205 amyloid-beta formation	IMP PMID:26280335 An atomic structure of human γ-secretase.	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving	IDA PMID:26280335 An atomic structure of human γ-secretase.	ACCEPT	Summary: PSEN1 is the catalytic presenilin subunit of gamma-secretase, a membrane-embedded aspartyl protease complex that cleaves type I membrane-protein substrates including APP and Notch. Reason: This annotation reflects the core evolved function of PSEN1 in regulated intramembrane proteolysis. Structural and biochemical evidence identify presenilin as the catalytic component of mature gamma-secretase.
GO:0042982 amyloid precursor protein metabolic process	IDA PMID:26280335 An atomic structure of human γ-secretase.	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0060828 regulation of canonical Wnt signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0070765 gamma-secretase complex	IDA PMID:26280335 An atomic structure of human γ-secretase.	ACCEPT	Summary: PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and PEN2. Reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other gamma-secretase subunits for mature protease activity.
GO:0035577 azurophil granule membrane	TAS Reactome:R-HSA-6798739	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0005515 protein binding	IPI PMID:21143716 Alzheimer's disease-associated ubiquilin-1 regulates preseni...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005886 plasma membrane	IDA PMID:21143716 Alzheimer's disease-associated ubiquilin-1 regulates preseni...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0016235 aggresome	IDA PMID:21143716 Alzheimer's disease-associated ubiquilin-1 regulates preseni...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0045121 membrane raft	IDA PMID:20299451 Human CRB2 inhibits gamma-secretase cleavage of amyloid prec...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0045893 positive regulation of DNA-templated transcription	IMP PMID:23794287 Presenilin-1 regulates the expression of p62 to govern p62-d...	MARK AS OVER ANNOTATED	Summary: Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation experiments rather than a clearly established normal PSEN1 core function. Reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology. Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream phenotype onto PSEN1.
GO:0016020 membrane	IDA PMID:22375059 Different effects of Sec61α, Sec62 and Sec63 depletion on tr...	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0060999 positive regulation of dendritic spine development	IMP PMID:21951279 Role of presenilin 1 in structural plasticity of cortical de...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0000776 kinetochore	IDA PMID:9298903 Alzheimer presenilins in the nuclear membrane, interphase ki...	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0005262 calcium channel activity	IMP PMID:16959576 Presenilins form ER Ca2+ leak channels, a function disrupted...	KEEP AS NON CORE	Summary: Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase, but this is secondary to the core gamma-secretase role. Reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity, but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
GO:0005790 smooth endoplasmic reticulum	IDA PMID:9632714 The presenilin 1 protein is a component of a high molecular ...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0005791 rough endoplasmic reticulum	IDA PMID:9632714 The presenilin 1 protein is a component of a high molecular ...	KEEP AS NON CORE	Summary: Broad or low-specificity subcellular location annotation for PSEN1. Reason: This location is too broad or too indirectly connected to the core gamma-secretase function to treat as a core annotation; retain only as non-core context or over-annotated where generic.
GO:0005794 Golgi apparatus	IDA PMID:9632714 The presenilin 1 protein is a component of a high molecular ...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005813 centrosome	IDA PMID:9298903 Alzheimer presenilins in the nuclear membrane, interphase ki...	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0008013 beta-catenin binding	IPI PMID:9632714 The presenilin 1 protein is a component of a high molecular ...	KEEP AS NON CORE	Summary: Specific beta-catenin binding annotation for PSEN1-associated complexes or interactors. Reason: The interaction is biologically relevant but secondary to the core gamma-secretase catalytic role; retain as non-core interaction context.
GO:0031965 nuclear membrane	IDA PMID:9298903 Alzheimer presenilins in the nuclear membrane, interphase ki...	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0032469 endoplasmic reticulum calcium ion homeostasis	IGI PMID:16959576 Presenilins form ER Ca2+ leak channels, a function disrupted...	KEEP AS NON CORE	Summary: Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase, but this is secondary to the core gamma-secretase role. Reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity, but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
GO:0043066 negative regulation of apoptotic process	IDA PMID:10805794 Behavioral alterations associated with apoptosis and down-re...	KEEP AS NON CORE	Summary: Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation. Reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies, but it is downstream or context-specific rather than the core molecular function.
GO:0070765 gamma-secretase complex	IDA PMID:10801983 Presenilin 1 is linked with gamma-secretase activity in the ...	ACCEPT	Summary: PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and PEN2. Reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other gamma-secretase subunits for mature protease activity.
GO:0030165 PDZ domain binding	IPI PMID:10551805 Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein...	KEEP AS NON CORE	Summary: Specific PDZ domain binding annotation for PSEN1-associated complexes or interactors. Reason: The interaction is biologically relevant but secondary to the core gamma-secretase catalytic role; retain as non-core interaction context.
GO:0032469 endoplasmic reticulum calcium ion homeostasis	IDA PMID:17431506 Familial Alzheimer disease-linked mutations specifically dis...	KEEP AS NON CORE	Summary: Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase, but this is secondary to the core gamma-secretase role. Reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity, but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
GO:0005640 nuclear outer membrane	IDA PMID:9246482 Two homologous genes causing early-onset familial Alzheimer'...	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0005783 endoplasmic reticulum	IDA PMID:9246482 Two homologous genes causing early-onset familial Alzheimer'...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005794 Golgi apparatus	IDA PMID:9246482 Two homologous genes causing early-onset familial Alzheimer'...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0004175 endopeptidase activity	IDA PMID:8755489 Endoproteolysis of presenilin 1 and accumulation of processe...	MODIFY	Summary: Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase. Reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane aspartyl endopeptidase activity used for presenilin/gamma-secretase. Proposed replacements: aspartic endopeptidase activity, intramembrane cleaving
GO:0016020 membrane	TAS PMID:7596406 Cloning of a gene bearing missense mutations in early-onset ...	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.
GO:0005515 protein binding	IPI PMID:9689133 Presenilin 1 associates with glycogen synthase kinase-3beta ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:11076969 Identification of ubiquilin, a novel presenilin interactor t...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005515 protein binding	IPI PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515 is not informative about PSEN1 molecular function. Reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership, substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative than generic protein binding.
GO:0005783 endoplasmic reticulum	IDA PMID:15274632 Purification and characterization of the human gamma-secreta...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005794 Golgi apparatus	IDA PMID:15274632 Purification and characterization of the human gamma-secreta...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0005886 plasma membrane	IDA PMID:15274632 Purification and characterization of the human gamma-secreta...	ACCEPT	Summary: Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity in secretory, endosomal, and plasma-membrane compartments. Reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than a molecular function.
GO:0006509 membrane protein ectodomain proteolysis	IDA PMID:15274632 Purification and characterization of the human gamma-secreta...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0007220 Notch receptor processing	TAS PMID:15274632 Purification and characterization of the human gamma-secreta...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0016485 protein processing	IDA PMID:15274632 Purification and characterization of the human gamma-secreta...	KEEP AS NON CORE	Summary: Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage. Reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis terms carry the core functional information.
GO:0042987 amyloid precursor protein catabolic process	TAS PMID:15274632 Purification and characterization of the human gamma-secreta...	ACCEPT	Summary: PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptors. Reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be retained as core substrate-processing biology.
GO:0005739 mitochondrion	IDA PMID:12377771 The novel presenilin-1-associated protein is a proapoptotic ...	UNDECIDED	Summary: Evidence is not sufficient in the cached materials to decide whether this annotation should be retained for PSEN1. Reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence is incomplete or the annotation is unusual enough to require full-text review.
GO:0016020 membrane	TAS PMID:8878479 Increased amyloid-beta42(43) in brains of mice expressing mu...	MARK AS OVER ANNOTATED	Summary: Generic compartment annotation for PSEN1. Reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal, or gamma-secretase complex annotations.

📄 View Raw YAML

id: P49768
gene_symbol: PSEN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'Presenilin-1 is a multi-pass membrane aspartyl protease subunit of the gamma-secretase complex.
  After endoproteolytic maturation, presenilin-1 N- and C-terminal fragments assemble with nicastrin,
  APH1, and PEN2 in secretory and endosomal membranes to cleave type I membrane-protein substrates, including
  APP and Notch receptors. Through this intramembrane protease activity, PSEN1 contributes to amyloid-beta
  peptide generation, Notch receptor processing, and broader regulated intramembrane proteolysis. Additional
  evidence links presenilin holoprotein to endoplasmic-reticulum calcium leak/homeostasis and protein-trafficking
  interactions, but these are secondary to its core gamma-secretase catalytic role.'
alternative_products:
- name: 1 (I-467)
  id: P49768-1
- name: 2 (I-463)
  id: P49768-2
  sequence_note: VSP_005191
- name: 3 (I-374)
  id: P49768-3
  sequence_note: VSP_005191, VSP_005192
- name: 4 (Minilin)
  id: P49768-4
  sequence_note: VSP_007986, VSP_007987
- name: '5'
  id: P49768-5
  sequence_note: VSP_005192
- name: '6'
  id: P49768-6
  sequence_note: VSP_012288
- name: '7'
  id: P49768-7
  sequence_note: VSP_041440
existing_annotations:
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN1 is the catalytic presenilin subunit of gamma-secretase, which cleaves Notch receptors.
      The conserved PAINT annotation to Notch signaling is appropriate because Notch receptor processing
      is a core evolved function of presenilin/gamma-secretase biology.
    action: ACCEPT
    reason: Gamma-secretase cleaves Notch receptor substrates, and PSEN1 is the catalytic presenilin component
      of the complex. This is a core function, not only an Alzheimer disease context.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein
        (Abeta) precursor (APP) and the Notch receptor.
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: PSEN1 provides the catalytic aspartate protease activity of the gamma-secretase intramembrane
      protease complex. This molecular-function annotation is central and should be retained.
    action: ACCEPT
    reason: Structural and biochemical work places the PSEN1 catalytic aspartates in the membrane-embedded
      active site of human gamma-secretase.
    supported_by:
    - reference_id: PMID:26280335
      supporting_text: Among the two catalytic residues, Asp257 is located in the middle of TM6 slightly
        to the extracellular side, whereas Asp385 maps to the cytoplasmic side of TM7
- term:
    id: GO:0055074
    label: calcium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Presenilin proteins have experimental support for ER calcium leak channel activity independent
      of gamma-secretase, but this is a secondary function relative to PSEN1's core gamma-secretase protease
      role.
    action: KEEP_AS_NON_CORE
    reason: The annotation is biologically plausible and supported, but calcium homeostasis is best treated
      as a non-core presenilin activity for this review until the in-vivo physiological scope is separated
      from disease and cell-culture contexts.
    supported_by:
    - reference_id: PMID:16959576
      supporting_text: presenilins account for approximately 80% of passive Ca(2+) leak from the endoplasmic
        reticulum.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN1 participates in proteolytic processing of membrane proteins as the catalytic presenilin
      subunit of gamma-secretase. The term is broad, but the PAINT annotation captures a real core process.
    action: KEEP_AS_NON_CORE
    reason: The annotation is correct but less informative than the more specific membrane-protein ectodomain/intramembrane
      proteolysis and amyloid-beta/Notch processing annotations; retain as non-core broad process context.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: yeast cells suggest that PS, NCT, Aph-1, and Pen-2 are necessary and sufficient
        to reconstitute gamma-secretase activity.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN1/gamma-secretase cleaves type I membrane-protein substrates after ectodomain shedding,
      including APP and Notch receptor fragments. This is a core process annotation.
    action: ACCEPT
    reason: The annotation reflects PSEN1's conserved role in gamma-secretase substrate processing of
      membrane proteins.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: Gamma-secretase is a member of an unusual class of proteases with intramembrane
        catalytic sites.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN1-containing gamma-secretase cleaves APP-derived C-terminal fragments and generates amyloid-beta
      peptides. This is a core substrate processing outcome of PSEN1 gamma-secretase activity.
    action: ACCEPT
    reason: Purified gamma-secretase and structural studies support PSEN1 as the catalytic subunit responsible
      for APP cleavage leading to amyloid-beta production.
    supported_by:
    - reference_id: PMID:26280335
      supporting_text: Among these components, presenilin is responsible for the Aβ-producing proteolytic
        activity7,8.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: PSEN1 is a core component of the mature gamma-secretase complex, present as N- and C-terminal
      fragments with nicastrin, APH1, and PEN2.
    action: ACCEPT
    reason: This cellular-component annotation directly represents the complex in which PSEN1 performs
      its core catalytic role.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF,
        mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0000776
    label: kinetochore
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: 'Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage.'
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis
      terms carry the core functional information.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: 'PSEN1 is the catalytic presenilin subunit of gamma-secretase, a membrane-embedded aspartyl
      protease complex that cleaves type I membrane-protein substrates including APP and Notch.'
    action: ACCEPT
    reason: This annotation reflects the core evolved function of PSEN1 in regulated intramembrane proteolysis.
      Structural and biochemical evidence identify presenilin as the catalytic component of mature gamma-secretase.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0070588
    label: calcium ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: 'Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase,
      but this is secondary to the core gamma-secretase role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity,
      but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
- term:
    id: GO:0098794
    label: postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11083918
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12901838
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15322109
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16007100
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16641999
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18201567
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21115843
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21163940
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25394380
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26280335
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29611543
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30559186
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9223340
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0001921
    label: positive regulation of receptor recycling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0003407
    label: neural retina development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: &id001
    - id: GO:0042500
      label: aspartic endopeptidase activity, intramembrane cleaving
- term:
    id: GO:0004190
    label: aspartic-type endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: *id001
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005938
    label: cell cortex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: *id001
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0021549
    label: cerebellum development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0035253
    label: ciliary rootlet
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0042383
    label: sarcolemma
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0042734
    label: presynaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0043198
    label: dendritic shaft
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0043524
    label: negative regulation of neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0043589
    label: skin morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0044233
    label: mitochondria-associated endoplasmic reticulum membrane contact site
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: 'Specific cadherin binding annotation for PSEN1-associated complexes or interactors.'
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically relevant but secondary to the core gamma-secretase catalytic
      role; retain as non-core interaction context.
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: 'PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and
      PEN2.'
    action: ACCEPT
    reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other
      gamma-secretase subunits for mature protease activity.
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0098693
    label: regulation of synaptic vesicle cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0099175
    label: regulation of postsynapse organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0140249
    label: protein catabolic process at postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:2000059
    label: negative regulation of ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:10593990
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:8574969
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: EXP
  original_reference_id: PMID:25394380
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:25394380
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:10593990
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:8574969
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:9738936
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:10593990
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:11953314
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:11987239
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0045202
    label: synapse
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IMP
  original_reference_id: PMID:10508860
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:9689133
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:20445063
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IDA
  original_reference_id: PMID:24012003
  qualifier: is_active_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:28008308
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:24012003
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:24052308
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0007613
    label: memory
  evidence_type: IGI
  original_reference_id: PMID:11880515
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:28008308
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0050808
    label: synapse organization
  evidence_type: IGI
  original_reference_id: PMID:24012003
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: *id001
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: *id001
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12522139
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: involved_in
  review:
    summary: 'Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage.'
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis
      terms carry the core functional information.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: 'Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage.'
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis
      terms carry the core functional information.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: 'Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage.'
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis
      terms carry the core functional information.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:12297508
  qualifier: part_of
  review:
    summary: 'PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and
      PEN2.'
    action: ACCEPT
    reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other
      gamma-secretase subunits for mature protease activity.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: part_of
  review:
    summary: 'PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and
      PEN2.'
    action: ACCEPT
    reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other
      gamma-secretase subunits for mature protease activity.
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IDA
  original_reference_id: PMID:25542424
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26094765
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:26094765
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0070851
    label: growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:26094765
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:26200696
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:29061364
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:29061364
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IGI
  original_reference_id: PMID:29061364
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0045821
    label: positive regulation of glycolytic process
  evidence_type: IGI
  original_reference_id: PMID:29061364
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:25394380
  qualifier: involved_in
  review:
    summary: 'Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase,
      but this is secondary to the core gamma-secretase role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity,
      but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
- term:
    id: GO:0010975
    label: regulation of neuron projection development
  evidence_type: IMP
  original_reference_id: PMID:15004326
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IDA
  original_reference_id: PMID:15004326
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IDA
  original_reference_id: PMID:15004326
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IMP
  original_reference_id: PMID:17428795
  qualifier: enables
  review:
    summary: 'PSEN1 is the catalytic presenilin subunit of gamma-secretase, a membrane-embedded aspartyl
      protease complex that cleaves type I membrane-protein substrates including APP and Notch.'
    action: ACCEPT
    reason: This annotation reflects the core evolved function of PSEN1 in regulated intramembrane proteolysis.
      Structural and biochemical evidence identify presenilin as the catalytic component of mature gamma-secretase.
- term:
    id: GO:1990535
    label: neuron projection maintenance
  evidence_type: IGI
  original_reference_id: PMID:20445063
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0098609
    label: cell-cell adhesion
  evidence_type: IMP
  original_reference_id: PMID:11953314
  qualifier: acts_upstream_of_or_within
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1251997
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193682
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-205112
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220988
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3928656
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013361
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9017817
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839376
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2197556
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9604300
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:1905908
    label: positive regulation of amyloid fibril formation
  evidence_type: IGI
  original_reference_id: PMID:11880515
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
    proposed_replacement_terms: &id002
    - id: GO:0034205
      label: amyloid-beta formation
- term:
    id: GO:0004190
    label: aspartic-type endopeptidase activity
  evidence_type: NAS
  original_reference_id: PMID:24217950
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: *id001
- term:
    id: GO:0048143
    label: astrocyte activation
  evidence_type: IGI
  original_reference_id: PMID:20445063
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0002265
    label: astrocyte activation involved in immune response
  evidence_type: IGI
  original_reference_id: PMID:23152628
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:1904646
    label: cellular response to amyloid-beta
  evidence_type: IGI
  original_reference_id: PMID:23152628
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
    proposed_replacement_terms: *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10508860
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IMP
  original_reference_id: PMID:10508860
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0005790
    label: smooth endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:10508860
  qualifier: colocalizes_with
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IMP
  original_reference_id: PMID:10508860
  qualifier: part_of
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:26280335
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: enables
  review:
    summary: 'PSEN1 is the catalytic presenilin subunit of gamma-secretase, a membrane-embedded aspartyl
      protease complex that cleaves type I membrane-protein substrates including APP and Notch.'
    action: ACCEPT
    reason: This annotation reflects the core evolved function of PSEN1 in regulated intramembrane proteolysis.
      Structural and biochemical evidence identify presenilin as the catalytic component of mature gamma-secretase.
- term:
    id: GO:0042982
    label: amyloid precursor protein metabolic process
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: part_of
  review:
    summary: 'PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and
      PEN2.'
    action: ACCEPT
    reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other
      gamma-secretase subunits for mature protease activity.
- term:
    id: GO:0035577
    label: azurophil granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21143716
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21143716
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0016235
    label: aggresome
  evidence_type: IDA
  original_reference_id: PMID:21143716
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IDA
  original_reference_id: PMID:20299451
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:23794287
  qualifier: involved_in
  review:
    summary: 'Annotation reflects a phenotype or regulatory readout from Alzheimer-model, stress, or perturbation
      experiments rather than a clearly established normal PSEN1 core function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Do not use disease-progression or transgenic-model readouts as core evolved PSEN1 biology.
      Retain cautiously as non-core if plausible; mark over-annotated when the term projects a downstream
      phenotype onto PSEN1.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:22375059
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0060999
    label: positive regulation of dendritic spine development
  evidence_type: IMP
  original_reference_id: PMID:21951279
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0000776
    label: kinetochore
  evidence_type: IDA
  original_reference_id: PMID:9298903
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0005262
    label: calcium channel activity
  evidence_type: IMP
  original_reference_id: PMID:16959576
  qualifier: enables
  review:
    summary: 'Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase,
      but this is secondary to the core gamma-secretase role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity,
      but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
- term:
    id: GO:0005790
    label: smooth endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:9632714
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0005791
    label: rough endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:9632714
  qualifier: located_in
  review:
    summary: 'Broad or low-specificity subcellular location annotation for PSEN1.'
    action: KEEP_AS_NON_CORE
    reason: This location is too broad or too indirectly connected to the core gamma-secretase function
      to treat as a core annotation; retain only as non-core context or over-annotated where generic.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:9632714
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:9298903
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0008013
    label: beta-catenin binding
  evidence_type: IPI
  original_reference_id: PMID:9632714
  qualifier: enables
  review:
    summary: 'Specific beta-catenin binding annotation for PSEN1-associated complexes or interactors.'
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically relevant but secondary to the core gamma-secretase catalytic
      role; retain as non-core interaction context.
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IDA
  original_reference_id: PMID:9298903
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IGI
  original_reference_id: PMID:16959576
  qualifier: involved_in
  review:
    summary: 'Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase,
      but this is secondary to the core gamma-secretase role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity,
      but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:10805794
  qualifier: involved_in
  review:
    summary: 'Non-core PSEN1-associated neuronal, synaptic, adhesion, Wnt, or developmental process annotation.'
    action: KEEP_AS_NON_CORE
    reason: The annotation is plausible from presenilin/gamma-secretase biology or animal/cellular studies,
      but it is downstream or context-specific rather than the core molecular function.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:10801983
  qualifier: part_of
  review:
    summary: 'PSEN1 is a core component of the mature gamma-secretase complex with nicastrin, APH1, and
      PEN2.'
    action: ACCEPT
    reason: Complex membership is central to PSEN1 function because isolated presenilin requires the other
      gamma-secretase subunits for mature protease activity.
- term:
    id: GO:0030165
    label: PDZ domain binding
  evidence_type: IPI
  original_reference_id: PMID:10551805
  qualifier: enables
  review:
    summary: 'Specific PDZ domain binding annotation for PSEN1-associated complexes or interactors.'
    action: KEEP_AS_NON_CORE
    reason: The interaction is biologically relevant but secondary to the core gamma-secretase catalytic
      role; retain as non-core interaction context.
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IDA
  original_reference_id: PMID:17431506
  qualifier: acts_upstream_of_or_within
  review:
    summary: 'Presenilins have evidence for ER calcium leak/channel activity independent of gamma-secretase,
      but this is secondary to the core gamma-secretase role.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core/secondary presenilin biology; evidence supports ER calcium leak activity,
      but the in-vivo physiological scope is less settled than gamma-secretase proteolysis.
- term:
    id: GO:0005640
    label: nuclear outer membrane
  evidence_type: IDA
  original_reference_id: PMID:9246482
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:9246482
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:9246482
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:8755489
  qualifier: enables
  review:
    summary: 'Broad peptidase annotation for the PSEN1 catalytic role in gamma-secretase.'
    action: MODIFY
    reason: The general peptidase term is true in essence but should be replaced by the specific intramembrane
      aspartyl endopeptidase activity used for presenilin/gamma-secretase.
    proposed_replacement_terms: *id001
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:7596406
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9689133
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11076969
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: 'Generic protein binding annotation to PSEN1. The interaction may be real, but GO:0005515
      is not informative about PSEN1 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific relationships such as gamma-secretase complex membership,
      substrate processing, beta-catenin/cadherin interactions, or trafficking effects are more informative
      than generic protein binding.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: 'Subcellular localization consistent with PSEN1/gamma-secretase trafficking and activity
      in secretory, endosomal, and plasma-membrane compartments.'
    action: ACCEPT
    reason: Retain because endogenous presenilin/gamma-secretase is a multi-pass membrane complex found
      in ER, Golgi, endosomal, and cell-surface-related membranes; location is contextual rather than
      a molecular function.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: TAS
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: 'Broad protein-processing annotation for PSEN1/gamma-secretase substrate cleavage.'
    action: KEEP_AS_NON_CORE
    reason: Correct but broad; more specific gamma-secretase, APP, Notch, and intramembrane proteolysis
      terms carry the core functional information.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: 'PSEN1-containing gamma-secretase processes membrane-protein substrates, including APP-derived
      C-terminal fragments and Notch receptors.'
    action: ACCEPT
    reason: The process is a direct outcome of PSEN1 gamma-secretase catalytic activity and should be
      retained as core substrate-processing biology.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:12377771
  qualifier: located_in
  review:
    summary: 'Evidence is not sufficient in the cached materials to decide whether this annotation should
      be retained for PSEN1.'
    action: UNDECIDED
    reason: Use UNDECIDED rather than removing curator assertions because the available cached evidence
      is incomplete or the annotation is unusual enough to require full-text review.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:8878479
  qualifier: located_in
  review:
    summary: 'Generic compartment annotation for PSEN1.'
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is too broad to add useful information beyond the more specific membrane, ER/Golgi/endosomal,
      or gamma-secretase complex annotations.
core_functions:
- molecular_function:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  description: PSEN1 is the catalytic presenilin subunit of the mature gamma-secretase complex, a multi-pass
    membrane aspartyl protease that cleaves type I membrane-protein substrates after ectodomain shedding.
  directly_involved_in:
  - id: GO:0006509
    label: membrane protein ectodomain proteolysis
  - id: GO:0042987
    label: amyloid precursor protein catabolic process
  - id: GO:0034205
    label: amyloid-beta formation
  - id: GO:0007220
    label: Notch receptor processing
  - id: GO:0007219
    label: Notch signaling pathway
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0000139
    label: Golgi membrane
  - id: GO:0031901
    label: early endosome membrane
  - id: GO:0005886
    label: plasma membrane
  in_complex:
    id: GO:0070765
    label: gamma-secretase complex
  supported_by:
  - reference_id: PMID:15274632
    supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein
      (Abeta) precursor (APP) and the Notch receptor.
  - reference_id: PMID:15274632
    supporting_text: Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF,
      mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
  - reference_id: PMID:26280335
    supporting_text: Among these components, presenilin is responsible for the Aβ-producing proteolytic
      activity7,8.
proposed_new_terms: []
suggested_questions:
- question: Which PSEN1/gamma-secretase substrates are established normal in-vivo substrates across tissues,
    rather than inferred from disease models or overexpression systems?
  experts:
  - GO membrane proteolysis curators
  - gamma-secretase biology experts
- question: Should presenilin ER calcium leak/channel activity be curated as a conserved normal PSEN1
    molecular function, or kept as context-dependent non-core biology pending stronger in-vivo evidence?
  experts:
  - calcium signaling experts
  - neurobiology curators
- question: Which PSEN1 subcellular locations reflect endogenous active gamma-secretase complexes versus
    isolated holoprotein, overexpression, or interactor-specific experiments?
  experts:
  - cell biology curators
  - gamma-secretase complex experts
suggested_experiments:
- description: Use endogenous tagging and substrate-specific reporters in physiologic human neuronal and
    non-neuronal cells to separate active gamma-secretase localization from total PSEN1 holoprotein localization.
  hypothesis: Only a subset of PSEN1-positive compartments contain mature gamma-secretase complexes responsible
    for APP and Notch substrate cleavage.
  experiment_type: endogenous tagging/substrate reporter imaging
- description: Compare wild-type PSEN1, catalytically inactive PSEN1, and calcium-leak-defective PSEN1
    variants in knock-in cells or animal models under non-disease baseline conditions.
  hypothesis: ER calcium homeostasis is a separable normal presenilin activity rather than only a phenotype
    of familial Alzheimer variants or cellular stress.
  experiment_type: knock-in physiology/calcium imaging
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10508860
  title: Presenilin 1 suppresses the function of c-Jun homodimers via interaction with QM/Jif-1.
  findings: []
- id: PMID:10551805
  title: Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus
    of presenilin-1.
  findings: []
- id: PMID:10593990
  title: Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch.
  findings: []
- id: PMID:10801983
  title: Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state.
  findings: []
- id: PMID:10805794
  title: Behavioral alterations associated with apoptosis and down-regulation of presenilin 1 in the brains
    of p53-deficient mice.
  findings: []
- id: PMID:11076969
  title: Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein
    accumulation.
  findings: []
- id: PMID:11083918
  title: X11 alpha and x11 beta interact with presenilin-1 via their PDZ domains.
  findings: []
- id: PMID:11880515
  title: The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease.
  findings: []
- id: PMID:11953314
  title: A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates
    disassembly of adherens junctions.
  findings: []
- id: PMID:11987239
  title: Identification of the presenilins in hematopoietic cells with localization of presenilin 1 to
    neutrophil and platelet granules.
  findings: []
- id: PMID:12297508
  title: Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis
    of amyloid-beta precursor protein and Notch.
  findings: []
- id: PMID:12377771
  title: The novel presenilin-1-associated protein is a proapoptotic mitochondrial protein.
  findings: []
- id: PMID:12522139
  title: PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1.
  findings: []
- id: PMID:12763021
  title: APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity.
  findings: []
- id: PMID:12901838
  title: Presenilin-1 interacts directly with the beta-site amyloid protein precursor cleaving enzyme
    (BACE1).
  findings: []
- id: PMID:15004326
  title: 'A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison
    of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations.'
  findings: []
- id: PMID:15274632
  title: Purification and characterization of the human gamma-secretase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; exact abstract text supports
      gamma-secretase complex composition and APP/Notch substrate cleavage.
- id: PMID:15322109
  title: Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions
    and function of presenilin complexes.
  findings: []
- id: PMID:16007100
  title: Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem.
  findings: []
- id: PMID:16641999
  title: TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase
    activity.
  findings: []
- id: PMID:16959576
  title: Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked
    mutations.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports presenilin ER calcium
      leak biology, treated as non-core because the normal in-vivo scope is less
      settled than gamma-secretase proteolysis.
- id: PMID:17428795
  title: Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways
    of EphB2 receptor.
  findings: []
- id: PMID:17431506
  title: Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin
    1.
  findings: []
- id: PMID:18201567
  title: Cellular localization of Nicastrin affects amyloid beta species production.
  findings: []
- id: PMID:20299451
  title: Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein by binding to the presenilin
    complex.
  findings: []
- id: PMID:20445063
  title: Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
  findings: []
- id: PMID:21115843
  title: Activation and intrinsic gamma-secretase activity of presenilin 1.
  findings: []
- id: PMID:21143716
  title: Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 accumulation and aggresome
    formation.
  findings: []
- id: PMID:21163940
  title: Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.
  findings: []
- id: PMID:21951279
  title: Role of presenilin 1 in structural plasticity of cortical dendritic spines in vivo.
  findings: []
- id: PMID:22375059
  title: Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the
    endoplasmic reticulum of mammalian cells.
  findings: []
- id: PMID:23152628
  title: LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.
  findings: []
- id: PMID:23794287
  title: Presenilin-1 regulates the expression of p62 to govern p62-dependent tau degradation.
  findings: []
- id: PMID:24012003
  title: Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular
    prion protein.
  findings: []
- id: PMID:24052308
  title: Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity
    in an Alzheimer's model.
  findings: []
- id: PMID:24217950
  title: Ligand-dependent activation of EphA4 signaling regulates the proteolysis of amyloid precursor
    protein through a Lyn-mediated pathway.
  findings: []
- id: PMID:25394380
  title: G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates
    ER Ca(2+) Accumulation.
  findings: []
- id: PMID:25542424
  title: The miR-193a-3p regulated PSEN1 gene suppresses the multi-chemoresistance of bladder cancer.
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
- id: PMID:26094765
  title: Proton myo-inositol cotransporter is a novel γ-secretase associated protein that regulates Aβ
    production without affecting Notch cleavage.
  findings: []
- id: PMID:26200696
  title: Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes.
  findings: []
- id: PMID:26280335
  title: An atomic structure of human γ-secretase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text verified; supports PSEN1 catalytic aspartates
      in the human gamma-secretase transmembrane active site.
- id: PMID:27608597
  title: Specific combinations of presenilins and Aph1s affect the substrate specificity and activity
    of γ-secretase.
  findings: []
- id: PMID:28008308
  title: The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered
    Endoplasmic Reticulum Stress.
  findings: []
- id: PMID:29061364
  title: Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1
    mice.
  findings: []
- id: PMID:29611543
  title: Intracellular trafficking of TREM2 is regulated by presenilin 1.
  findings: []
- id: PMID:30559186
  title: Bax inhibitor 1 is a γ-secretase-independent presenilin-binding protein.
  findings: []
- id: PMID:7596406
  title: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
  findings: []
- id: PMID:8574969
  title: 'Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular
    membranes in mammalian cells.'
  findings: []
- id: PMID:8755489
  title: Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
  findings: []
- id: PMID:8878479
  title: Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
  findings: []
- id: PMID:9223340
  title: 'Interaction between amyloid precursor protein and presenilins in mammalian cells: implications
    for the pathogenesis of Alzheimer disease.'
  findings: []
- id: PMID:9246482
  title: Two homologous genes causing early-onset familial Alzheimer's disease.
  findings: []
- id: PMID:9298903
  title: Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest
    a role in chromosome segregation.
  findings: []
- id: PMID:9632714
  title: The presenilin 1 protein is a component of a high molecular weight intracellular complex that
    contains beta-catenin.
  findings: []
- id: PMID:9689133
  title: Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau.
  findings: []
- id: PMID:9738936
  title: Direct association of presenilin-1 with beta-catenin.
  findings: []
- id: Reactome:R-HSA-1251997
  title: Cleavage of ERBB4m80 by gamma-scretase complex
  findings: []
- id: Reactome:R-HSA-193682
  title: gamma-secretase cleaves the p75NTR transmembrane domain
  findings: []
- id: Reactome:R-HSA-205112
  title: gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
  findings: []
- id: Reactome:R-HSA-2220988
  title: NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-3928656
  title: gamma-secretase cleaves EPHB2
  findings: []
- id: Reactome:R-HSA-6798739
  title: Exocytosis of azurophil granule membrane proteins
  findings: []
- id: Reactome:R-HSA-9013361
  title: NEXT3 is cleaved to produce NICD3
  findings: []
- id: Reactome:R-HSA-9017817
  title: Gamma-secretase cleaves YBX1:NOTCH3
  findings: []
- id: Reactome:R-HSA-9839376
  title: TGFBR3(784-851) degradation
  findings: []
- id: Reactome:R-NUL-2197556
  title: Gamma-secretase complex cleaves mNEXT2
  findings: []
- id: Reactome:R-NUL-9604300
  title: Gamma-secretase cleaves Notch4
  findings: []

Gene Description

Existing Annotations Review

Core Functions

PSEN1 is the catalytic presenilin subunit of the mature gamma-secretase complex, a multi-pass membrane aspartyl protease that cleaves type I membrane-protein substrates after ectodomain shedding.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

PSEN1 Notes

2026-06-19

2026-06-20 Second-Pass Review Notes

📄 View Raw YAML