GBA1 encodes acid glucosylceramidase, a lysosomal glycosidase that hydrolyzes glucosylceramide to ceramide and glucose. Saposin C and the lipid membrane environment facilitate substrate access and enzyme association with the lumenal membrane surface. LIMP-2/SCARB2 binds GBA1 and delivers it through the secretory pathway to lysosomes. This chemistry supports glycosphingolipid turnover and ceramide production, including lipid processing needed for the epidermal permeability barrier. GBA1 also hydrolyzes other glycosides and can transfer glucose from glucosylceramide to cholesterol under suitable substrate conditions. Loss of function causes Gaucher disease and perturbs lysosomal lipid homeostasis; GBA1 variants also increase susceptibility to Parkinson disease. The long and short initiation products can both generate active lysosomal enzyme.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004336 galactosylceramidase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: GalCer-analog hydrolysis is measured, but physiological GalCer clearance is unestablished. Reason: The reported GBA1 assay hydrolyzes C6-NBD-GalCer at approximately 200-fold lower activity than C6-NBD-GlcCer; this compares GBA1 substrates, not GBA1 with GALC. Human lysosomal GALC (P54803) is the dedicated GalCer hydrolase associated with Krabbe disease. The GBA1 chemistry is real, but physiological GalCer clearance is unestablished, supporting MARK_AS_OVER_ANNOTATED. Supporting Evidence: |
| GO:0004348 glucosylceramidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Glucosylceramide hydrolysis is the conserved catalytic function of GBA1. Reason: Human substrate assays independently establish the reaction. The actual PTHR11069 tree places the sequence-verified human target below the asserted ancestral IBD node, with no recorded loss on its path. The target appearing among descendant experimental sources is legitimate PAINT evidence, not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001667738 SUPPORTS TRANSFER Actual ancestral AN7 carries the glucosylceramidase IBD; sequence-verified P04062 is descendant AN30. Experimental descendants include the human target, and the inspected family file contains no NOT/IRD/IKR exception. The tree metadata is preserved literally; it is not used to assign human taxonomy or a new evolutionary date. |
| GO:0004348 glucosylceramidase activity | IDA PMID:16293621 Analyses of variant acid beta-glucosidases: effects of Gauch... | ACCEPT | Summary: Purified GCase variants retain or alter the established catalytic activity. Reason: The authentic abstract describes purified, insect-cell-expressed variants and kinetic, inhibitor and activator measurements. Human patient variants and selected mouse variants are distinguished in the source; these engineered substitutions are not natural splice products. The direct activity assignment agrees with independent glucosylceramide hydrolysis. |
| GO:0004348 glucosylceramidase activity | IDA PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: GBA1 cleaves glucosylceramide in the ceramide salvage pathway. Reason: The authentic abstract reports human MCF-7 GBA1 knockdown, reduced enzyme activity and impaired stimulus-dependent GlcCer loss; GBA1 overexpression increases ceramide. These observations support the core hydrolysis reaction without implying that GBA1 itself performs the subsequent sphingosine deacylation or reacylation steps. Supporting Evidence: PMID:19279011 which hydrolyzes glucosylceramide to form lysosomal ceramide |
| GO:0004348 glucosylceramidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: The study directly measures glucosylceramide hydrolysis by recombinant GBA1. Reason: Original Methods assay radiolabelled GlcCer and chromatographically separate its products; recombinant therapeutic GBA1 is tested alongside human and mouse materials. This directly supports the GlcCer hydrolase claim. The same study also examines bile-acid glucosides, which must not be confused with the GlcCer substrate. Supporting Evidence: |
| GO:0004348 glucosylceramidase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | ACCEPT | Summary: GlcCer-dependent transfer complements the hydrolase claim. Reason: The accessible abstract supports transfer using GlcCer; independent natural-substrate hydrolysis grounds the core activity. Full Methods were not inspected. |
| GO:0004348 glucosylceramidase activity | IDA PMID:9201993 Effect of saposins A and C on the enzymatic hydrolysis of li... | ACCEPT | Summary: Glucosylceramidase hydrolyses membrane-associated glucosylceramide with saposin assistance. Reason: The authentic abstract reports turnover of GlcCer in phospholipid liposomes and distinct saposin A/C effects. Saposin C promotes enzyme association with the lipid surface; this supports catalysis without making GBA1 a transmembrane transporter. The abstract does not by itself identify every protein preparation or modern product suffix. Supporting Evidence: |
| GO:0004348 glucosylceramidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic sources identify the established glucosylceramidase activity. Reason: The mapped reaction agrees with human GBA1 biochemical studies and the experimentally grounded ancestral activity. All distinct incoming identifiers are retained in supporting_entities; the raw archive also preserves repeated occurrences. Acceptance rests on direct target chemistry, not the number of combined mappings. |
| GO:0004348 glucosylceramidase activity | IMP PMID:15916907 Use of fluorescent substrates for characterization of Gauche... | ACCEPT | Summary: Variant-dependent substrate turnover supports glucosylceramidase activity. Reason: The authentic abstract reports testing GBA variants against fluorescent glucosylceramide and glucoside substrates in a heterologous expression system. These activity comparisons support the enzyme assignment. Full Methods and exact modern natural-product equivalence were not established from that abstract; independent natural-substrate assays support the core reaction. |
| GO:0004348 glucosylceramidase activity | IMP PMID:21700325 Gaucher disease glucocerebrosidase and Ξ±-synuclein form a bi... | ACCEPT | Summary: Neuronal GCase loss reduces glucosylceramide turnover. Reason: Selected original Results distinguish primary-neuron knockdown from human Gaucher iPSC-derived neurons and report reduced GCase activity with lipid accumulation. This supports the catalytic claim in the retained neuronal extension context. The pathogenic protein-clearance effects are separate downstream observations, not a new substrate specificity. Supporting Evidence: |
| GO:0004348 glucosylceramidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: GBA1-deficient materials and purified-enzyme assays support the assigned hydrolase function. Reason: The original study combines patient and mouse deficiency comparisons with a direct recombinant-enzyme control. Its distinct GlcCer assay establishes the core activity; imperfect inhibitor specificity and compensatory GBA1 elevation in Gba2-deficient cells are explicitly reported, so inhibitor effects alone are not treated as exclusive identification. Supporting Evidence: |
| GO:0004348 glucosylceramidase activity | IMP PMID:23580063 Loss of Ξ²-glucocerebrosidase activity does not affect alpha-... | ACCEPT | Summary: The perturbation study directly monitors loss of GCase enzyme activity. Reason: Original Methods use a fluorogenic glucoside assay in human SH-SY5Y and rat cortical cultures, and CBE markedly suppresses measured activity. This is an activity perturbation, not a direct natural-GlcCer assay in that experiment; independent natural-substrate biochemistry supports the specific enzyme assignment. Its negative alpha-synuclein results do not negate GBA1 catalysis. |
| GO:0004348 glucosylceramidase activity | IMP PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | ACCEPT | Summary: Gaucher-cell enzyme measurements support GBA1 catalytic activity. Reason: The authentic abstract reports changes in GCase activity and protein abundance after miRNA perturbations in patient fibroblasts, including altered LIMP-2-dependent trafficking. This documents regulation of an established enzyme, not miRNA processing or a transcriptional function of GBA1. Exact full-text assay conditions remain outside this abstract reading. |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000120 | MODIFY | Summary: Resolve receptor binding to the identified scavenger receptor LIMP-2/SCARB2. Reason: The mouse donor has experimentally supported GCaseβLIMP-2 binding, and independent human GBA1 experiments establish the same interaction. Scavenger receptor binding is a verified is_a child of the incoming term and describes the partner more specifically. This does not assign receptor signaling or transport activity to the GBA1 cargo. Proposed replacements: scavenger receptor binding Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase |
| GO:0005102 signaling receptor binding | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | MODIFY | Summary: Specify LIMP-2/SCARB2 binding while retaining the mouse-donor provenance. Reason: The authentic source abstract identifies LIMP-2 as the binding and lysosomal sorting receptor; its mouse deficiency/rescue experiments remain donor evidence. The independent human-construct study supports the specific scavenger-receptor interaction. Full Methods of this cited paper were not inspected, and no natural-product-exclusive binding is inferred. Proposed replacements: scavenger receptor binding |
| GO:0005124 scavenger receptor binding | IPI PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | KEEP AS NON CORE | Summary: Retain the specific interaction with the lysosomal sorting receptor. Reason: Selected original Methods and Results identify human GBA1 constructs, purified binding components and LIMP-2-dependent sorting. This supports the incoming Q14108 interaction. GBA1 is the transported enzymatic cargo, not the receptor or transmembrane transporter; the interaction assists deployment of its catalytic function. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21098288 Decreased glucocerebrosidase activity in Gaucher disease par... | MODIFY | Summary: Specify binding to the TCP1/TRiC folding chaperone. Reason: Original human-fibroblast Results report reciprocal GCase/TCP1 co-immunoprecipitation and reduced association in Gaucher cells; the retained partner is TCP1. The chaperone-binding term captures the partner role more informatively than generic protein binding. GBA1 remains the client, with no folding or ubiquitin-ligase activity assigned to it. Proposed replacements: protein-folding chaperone binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24162852 Structure of LIMP-2 provides functional insights with implic... | MODIFY | Summary: Replace generic protein binding with the documented scavenger-receptor interaction. Reason: The authentic abstract identifies the GCase-binding helical region of LIMP-2, and the incoming partner is SCARB2/Q14108. Independent human-target experiments support this specific interaction. The other receptors and their lipid-tunnel activities in the paper are not transferred to GBA1; original full Methods remain outside this reading. Proposed replacements: scavenger receptor binding |
| GO:0005515 protein binding | IPI PMID:27789271 Progranulin Recruits HSP70 to Ξ²-Glucocerebrosidase and Is Th... | REMOVE | Summary: Omit generic protein binding while preserving the demonstrated GBA1βPGRN interaction. Reason: Recombinant binding and cellular assays directly support the named interaction. PGRN recruits the HSP70 chaperone; those results do not establish that PGRN itself has the protein-folding-chaperone role required for the proposed refinement. Generic protein binding adds no informative molecular-function assertion under the review policy. Removal concerns that uninformative term, not the reality of GBA1βPGRN binding or its trafficking context. Supporting Evidence: PMID:27789271 PGRN binds directly to GCase |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain extracellular detection as a secondary localization. Reason: The actual mouse donor has direct plasma enzyme-activity evidence in PMID:19710420, including wild-type animals. This supports the literal ortholog inference without treating the mouse assay as direct human evidence or assigning a secretion mechanism. Human urine-fraction proteomics independently supports extracellular detection. |
| GO:0005764 lysosome | IEA GO_REF:0000107 | ACCEPT | Summary: Lysosomal localization is central to GBA1 function. Reason: The mouse source includes direct localization evidence, and human GBA1 trafficking experiments independently establish the lysosomal destination. Keep the informative organelle claim alongside membrane and lumen rows; this is not an unsupported inference from the enzyme name alone. |
| GO:0005764 lysosome | IMP PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: Human GBA1 is delivered to lysosomes through LIMP-2-dependent trafficking. Reason: The selected original experiments connect the GBA1βLIMP-2 interaction to intracellular delivery and lysosomal function. Human target constructs and patient-cell observations support this organelle claim; receptor-deficient mouse comparisons remain separate provenance. Supporting Evidence: |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: The membrane-proteomics attribution agrees with independently supported peripheral association. Reason: The authentic abstract describes integral and associated proteins in purified placental lysosomal membranes. The target table was not inspected, so no peptide count or GBA1-specific fractionation result is invented. Retain the curatorβs HDA attribution with independent GBA1 membrane-substrate and LIMP-2 evidence. |
| GO:0005765 lysosomal membrane | IDA PMID:17187079 Structure of acid beta-glucosidase with pharmacological chap... | ACCEPT | Summary: Retain the curated lysosomal-membrane localization with independent biochemical support. Reason: The authentic abstract establishes restored lysosomal trafficking of mutant GCase after chaperone treatment, but does not expose the full subcompartment assay. Independent membrane-substrate and receptor-binding evidence supports the localization as peripheral association. The inaccessible original Methods are not reconstructed from the abstract. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: GBA1 associates peripherally with lysosomal membranes. Reason: Independent target evidence supports a lumen-facing hydrolase associated with membrane-presented substrate and partner proteins. The combined ARBA, ortholog and UniProt location sources recover this claim; they do not imply that GBA1 spans the bilayer. |
| GO:0005765 lysosomal membrane | IPI PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | ACCEPT | Summary: GBA1 binding to its lysosomal membrane receptor supports the complex-associated location. Reason: The original structure and mutagenesis directly resolve the GBA1βLIMP-2 interface. The experiment used secreted soluble LIMP-2 residues 36β431, so the structure itself does not demonstrate a native bilayer or residence time in lysosomes. Independent trafficking and lipid-surface evidence supports the membrane-associated annotation without assuming permanent receptor binding at acidic pH. |
| GO:0005765 lysosomal membrane | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: The mouse-donor localization is consistent with human lysosomal-membrane association. Reason: The literal donor carries direct PMID:18022370 localization evidence. Human GBA1βLIMP-2 and lipid-substrate experiments independently support the same location. Retention does not turn GBA1 into an integral membrane transporter or transfer receptor activity to its cargo. |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-1605591 | ACCEPT | Summary: The curated human reaction explicitly places GBA1 at the lysosomal membrane. Reason: The actual Reactome chain is R-HSA-1605591 catalyst R-HSA-1605675, containing human GBA1 R-HSA-1605775, UniProt P04062 chain 40β536, in the lysosomal membrane compartment. This is the saposin-C-associated catalytic context, not evidence for a GBA1 transmembrane segment or for every declared natural product. Supporting Evidence: Reactome:R-HSA-1605591 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The electronic ER inference is supported as a trafficking location. Reason: The recorded mouse source has direct localization evidence rather than only a reciprocal electronic assertion. Human receptor-complex biology supports the same biosynthetic route. Keep ER as a non-core location without narrowing it to an unmeasured subcompartment. ORGANELLES check (2026-11-05): the Ensembl projection's mouse source (P17439) rests on a mouse IDA ER annotation from PMID:27789271 (checked in QuickGO), in which GCase co-localizes with progranulin in the ER and lysosome by double-label immunogold TEM, and the human GCase/LIMP-2 transport complex is described as forming in the ER (PMID:40159502). GBA1 is a soluble lumenal hydrolase with a cleaved signal peptide (residues 1-39) and no KDEL-like retrieval motif, so the ER pool is biosynthetic transit, kept as non-core because untagged GCase is seen there by immunogold and the LIMP-2 receptor complex assembles there; MARK_AS_OVER_ANNOTATED was considered and rejected on that basis. No ER lumen term is added, since a transit pool does not establish residence (ER batch 1 rule). Supporting Evidence: PMID:27789271 Double labeling immunogold TEM also showed that PGRN co-localized with GCase in the ER and lysosome PMID:40159502 The GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome together |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain ER localization during biosynthetic trafficking. Reason: The mouse donorβs direct source reports GCase colocalization in ER-containing traffic compartments, consistent with human GBA1 entering the secretory pathway before lysosomal delivery. The location is peripheral to its principal lysosomal hydrolysis and does not establish an ER-specific catalytic role. ORGANELLES check (2026-11-05): the ISS donor is the same mouse entry (P17439) as the Ensembl IEA row, whose only ER annotation is the IDA from PMID:27789271 (checked in QuickGO), so both rows carry one transit claim and keep the same non-core action; ER retention and ERAD of misfolded Gaucher mutants (the ER retention mutant rescued by LIMP-2 in PMID:18022370) is a quality-control pool of mutant protein and is not used as support here. No ER lumen term is added. Supporting Evidence: PMID:27789271 Double labeling immunogold TEM also showed that PGRN co-localized with GCase in the ER and lysosome PMID:40159502 The GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome together |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The Golgi electronic transfer is supported as a secondary localization. Reason: Direct donor localization and the GBA1βLIMP-2 transport route support this compartment. Retention does not make the Golgi a second principal site of GBA1 catalysis; no product-specific localization is inferred. |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain Golgi association along the lysosomal delivery route. Reason: The actual mouse donor source reports GCase in Golgi traffic compartments. This positive localization is consistent with the established transport route, but does not place the principal lipid-hydrolysis function in the Golgi. The source organism and trafficking scope remain explicit. |
| GO:0005802 trans-Golgi network | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the trans-Golgi inference with its donor and trafficking limits. Reason: The electronic row rests on a mouse source with direct compartment evidence. The independently described GBA1βLIMP-2 route is consistent with that placement. No exclusive retention, local catalytic function or natural-product assignment follows from the transfer. |
| GO:0005802 trans-Golgi network | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The trans-Golgi network is a supported trafficking compartment. Reason: The actual mouse donor source explicitly reports GCase colocalization in the trans-Golgi network, distinct from lysosomal delivery. Keep the human ortholog inference as a non-core transit location, without claiming a trans-Golgi-specific substrate reaction. |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000002 | TOO GENERAL | Summary: The general sphingolipid process is redundant with retained glucosylceramide catabolism. Reason: The verified ontology ancestry places glucosylceramide catabolism under sphingolipid metabolism. GBA1 directly performs that specific hydrolytic step, already retained with biochemical and cellular support. The InterPro inference is biologically correct but adds no distinct process information. |
| GO:0006680 glucosylceramide catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Glucosylceramide catabolism is a conserved core process executed by GBA1. Reason: GBA1 itself cleaves the glucosylceramide substrate, rather than merely being required for another enzyme to act. The actual PAINT IBD for this process lies on the verified human target lineage, without a recorded loss. Human substrate assays and cellular perturbations independently support the inherited function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001667738 SUPPORTS TRANSFER Actual AN7 process IBD is ancestral to exact human P04062 AN30. Experimentally supported descendants include human target; no NOT/IRD/IKR family exception was found. Literal deep-node metadata is preserved without inferring a new date or human taxonomy. |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:16293621 Analyses of variant acid beta-glucosidases: effects of Gauch... | ACCEPT | Summary: Substrate-dependent enzyme measurements support direct glucosylceramide catabolism. Reason: The authentic abstract describes purified GCase variants and altered catalytic properties. Together with independent natural-substrate biochemistry, this supports the process executed by the enzyme. Engineered human and mouse variants in the source are not equated with current natural products, and full Methods were not inspected. |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | ACCEPT | Summary: GBA1 directly consumes GlcCer. Reason: Cleavage of the glucose donor is catalytic participation. Independent hydrolysis evidence supports catabolism alongside the alternate acceptor route. |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:9201993 Effect of saposins A and C on the enzymatic hydrolysis of li... | ACCEPT | Summary: GBA1 directly degrades membrane-associated glucosylceramide. Reason: The authentic abstract reports GlcCer turnover in phospholipid liposomes with saposin assistance. The enzyme executes the catabolic hydrolysis, while saposins facilitate access to the lipid surface. This establishes the process without assigning saposin function or transmembrane transport to GBA1. Supporting Evidence: |
| GO:0006680 glucosylceramide catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic sources recover the established glucosylceramide-degradation process. Reason: Direct target chemistry and cellular substrate-turnover evidence support the inferred process. The incoming ARBA and ortholog provenance is preserved literally; multiple source identifiers are not counted as separate experiments. GBA1 is the catalytic participant in the hydrolytic step. |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: Human GBA1 directly degrades glucosylceramide in the salvage pathway. Reason: Original human MCF-7 experiments combine GBA1 knockdown and overexpression with substrate turnover. GBA1 performs the GlcCer-to-ceramide step; subsequent ceramide deacylation and sphingosine reacylation belong to other enzymes. This direct step supports the specific catabolic process. Supporting Evidence: |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:21700325 Gaucher disease glucocerebrosidase and Ξ±-synuclein form a bi... | ACCEPT | Summary: GCase loss impairs glucosylceramide turnover in neuronal systems. Reason: Selected original Results report lipid accumulation after GCase depletion and in human Gaucher iPSC-derived neurons. These observations support the enzymeβs established catabolic step in the literal neuronal extension context. Downstream protein-accumulation phenotypes do not change the identity of its lipid substrate. Supporting Evidence: |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:24022302 Functional analysis of 11 novel GBA alleles. | ACCEPT | Summary: Loss of GBA1 activity is consistent with impaired glucosylceramide catabolism. Reason: The authentic abstract reports functional testing of GBA alleles and reduced activity in transfected cells. It does not establish a natural-product-specific process or expose all assay details. Independent GlcCer substrate studies support the core process, so the experimental attribution is retained without inventing a lipid-accumulation assay in this paper. |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | ACCEPT | Summary: The cellular activity study concerns the established glucosylceramide-degrading enzyme. Reason: The accessible abstract measures regulation of GCase activity and trafficking in patient fibroblasts. Specific catabolic participation is supported by independent substrate biochemistry, not inferred from miRNA effects alone. Full-text substrate measurements and exact modern-product scope remain unverified here. |
| GO:0006914 autophagy | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain the experimentally grounded autophagic contribution as a secondary cellular role. Reason: The mouse-donor chain has perturbation evidence, and independent human-cell work supports altered autophagic flux after GCase loss. This retains a context-dependent lysosomal contribution without making GBA1 an autophagosome assembly factor or extending the effect to every cell type. Supporting Evidence: |
| GO:0006914 autophagy | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | KEEP AS NON CORE | Summary: GCase deficiency alters autophagic turnover in the tested cellular systems. Reason: Selected original experiments support impaired flux in human SH-SY5Y cells and mouse neurons, with differing fibroblast responses. Retain the positive perturbation result as secondary to lysosomal lipid metabolism; neither a universal flux defect nor direct autophagosome-building activity is established. Supporting Evidence: |
| GO:0007005 mitochondrion organization | IMP NOT PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | KEEP AS NON CORE | Summary: Preserve the reported negative mitochondrial-organization result within its neuronal culture context. Reason: The original study found normal mitochondrial morphology and distribution in the differentiated lines, including N370S heterozygous cultures. This is a bounded NOT observation with residual GCase activity, not a demonstration that GBA1 can never influence mitochondria. Retain the literal negation and experimental provenance without promoting an absence claim to the core. Supporting Evidence: |
| GO:0007040 lysosome organization | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 contributes to lysosomal organization through its lipid-dependent cellular role. Reason: The donor inference is supported by experimental changes in lysosomal homeostasis after GCase perturbation. Retention does not identify GBA1 as a structural lysosome assembly component; its established enzymatic role and the measured organelle effects remain distinct. Supporting Evidence: |
| GO:0007040 lysosome organization | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | KEEP AS NON CORE | Summary: Retain the observed lysosomal-organization effects with the reformation mechanism qualified. Reason: The original study measures acidic-vesicle, Rab7 and signaling endpoints and interprets them as altered lysosome reformation. Those effects support a secondary organization role, but direct tubulation or a dedicated reformation activity was not established. No new reformation-specific term is asserted. Supporting Evidence: |
| GO:0008203 cholesterol metabolic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: Retain the cholesterol-modifying reaction. Reason: Recombinant-enzyme and human-cell observations support glucosylation. Physiological direction remains conditional, as detailed in the source guide. Supporting Evidence: |
| GO:0008203 cholesterol metabolic process | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: Reversible sterol glucosylation and hydrolysis support cholesterol metabolism. Reason: Selected original experiments distinguish GBA1-mediated sterol-glycoside turnover from GBA2 and show dependence on local substrate availability. GBA1 directly performs a chemical step; disease-associated lipid abundance is supporting context, not a separate demonstration of cholesterol transport. Supporting Evidence: |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain secondary cholesterol metabolism. Reason: Glucosyl transfer and hydrolysis directly alter sterol conjugation. This does not establish cholesterol transport or generalized homeostasis. |
| GO:0008422 beta-glucosidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | KEEP AS NON CORE | Summary: Purified GBA1 hydrolyses glucosylated bile-acid substrates. Reason: Original Methods and Results separately assay bile-acid glucosides and GlcCer using recombinant GBA1. The former support this broader beta-glucosidase activity beyond its core lipid substrate. Substrate selectivity and assay conditions remain important; this is not evidence of universal glucoside clearance. Supporting Evidence: |
| GO:0008422 beta-glucosidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain the enzymeβs measured beta-glucoside substrate breadth. Reason: The mouse donor and independent recombinant GBA1 assays support beta-glucoside hydrolysis, including glucosylated bile acids. Although steryl-beta-glucosidase is a narrower descendant, it does not capture the additional bile-acid substrates measured here. Retention describes secondary chemistry without implying that every beta-glucoside is an efficient physiological substrate. Supporting Evidence: |
| GO:0008422 beta-glucosidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | KEEP AS NON CORE | Summary: Deficiency comparisons corroborate beta-glucoside turnover. Reason: The original study combines human and mouse deficiency comparisons with recombinant-enzyme assays. Those results support GBA1 contribution to bile-acid-glucoside hydrolysis while retaining the reported compensation and inhibitor-selectivity limits. The direct enzyme controls distinguish this from an inference based only on loss-of-function phenotypes. Supporting Evidence: |
| GO:0009247 glycolipid biosynthetic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: Retain the bounded sterol-glycoside synthesis context. Reason: GBA1 performs the measured synthesis. The parent definition/hierarchy discrepancy described in the source guide remains unresolved; no unverified child term replaces it. Supporting Evidence: |
| GO:0009247 glycolipid biosynthetic process | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: GBA1-mediated transglucosylation can generate a sterol glycolipid. Reason: The original study demonstrates the transfer reaction and its substrate-dependent reversibility. This supports conditional glycolipid synthesis, while its separate GBA2 manipulations and plasma measurements are not treated as GBA1-only biosynthetic assays. No additional process term is manufactured. The current GO:0009247 definition narrowly names diacylglycerol glycolipids, whereas its verified is_a children also include glycosphingolipid and dolichol-linked biosynthesis. Retain this non-core sterol-glycoside context provisionally and flag that definition/hierarchy scope for ontology clarification; no unverified specific child is substituted. Supporting Evidence: |
| GO:0009247 glycolipid biosynthetic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 can synthesize a glycolipid through transglucosylation. Reason: Cholesteryl glucoside formation is a directly demonstrated GBA1 reaction. This does not make GBA1 the UDP-glucose-dependent glucosylceramide synthase or imply constitutive net synthesis. The current GO:0009247 definition narrowly names diacylglycerol glycolipids, whereas its verified is_a children also include glycosphingolipid and dolichol-linked biosynthesis. Retain this non-core sterol-glycoside context provisionally and flag that definition/hierarchy scope for ontology clarification; no unverified specific child is substituted. |
| GO:0009267 cellular response to starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the donor-supported autophagic response to starvation. Reason: The actual mouse knockout study compares serum/amino-acid starvation responses and measures LC3 and p62 changes. Residual induction persists in deficient cells, but the response is impaired. This supports a conditional lysosomal contribution to starvation adaptation, not nutrient sensing or an all-or-none requirement. Supporting Evidence: |
| GO:0009268 response to pH | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain pH-sensitive epidermal lipid processing with the rat-donor scope. Reason: The authentic donor abstract links neonatal stratum-corneum pH to beta-glucocerebrosidase activity and barrier recovery; acidification improves recovery. The original full text remains inaccessible. Independent enzymology supports pH-dependent GBA1 catalysis, so the whole claim is credible without assigning GBA1 a pH-sensor or proton-pump role. |
| GO:0016241 regulation of macroautophagy | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Retain modulation of macroautophagic function as a secondary role. Reason: Actual neuronal flux and lysosomal studies support GBA1-dependent changes in macroautophagy. The electronic assertion is consistent with those experiments; it does not identify GBA1 as an autophagosome assembly factor or imply uniform effects across cell types. |
| GO:0016241 regulation of macroautophagy | TAS PMID:26388395 Mitochondrial dysfunction associated with glucocerebrosidase... | KEEP AS NON CORE | Summary: The review supports secondary effects on macroautophagic flux. Reason: The cited synthesis distinguishes macroautophagy from chaperone-mediated autophagy and summarizes direct flux studies. Independent primary experiments substantiate the regulatory claim while leaving the lipid-mediated mechanism and cell-context differences explicit. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000107 | TOO GENERAL | Summary: Hydrolase activity is correct but redundant with the retained specific catalytic functions. Reason: The verified ontology ancestry places glucosylceramidase and steryl-beta-glucosidase under hydrolase activity. Both specific activities are retained with direct biochemical support, so this electronic parent contributes no additional functional information. This is a specificity judgment, not rejection of the mouse donor or of hydrolysis. |
| GO:0019377 glycolipid catabolic process | NAS PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | TOO GENERAL | Summary: The broad glycolipid catabolic process is covered by the specific retained GlcCer pathway. Reason: Current typed ontology ancestry places the accepted glucosylceramide catabolic process under this term. The broader NAS assertion is biologically sound but adds no distinct process to the retained specific catalytic role. The original ComplexPortal reference remains unchanged. |
| GO:0023021 termination of signal transduction | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: Retain the lipid-mediated attenuation of p38 signaling. Reason: Human-cell GBA1 knockdown prolongs stimulated p38 phosphorylation. GBA1 catalyzes production of the ceramide signal at a termination control point, a role included by the GO:0023021 comment; downstream phosphatases execute p38 dephosphorylation. This supports a source-specific non-core role without assigning protein-phosphatase activity to GBA1. Supporting Evidence: |
| GO:0030163 protein catabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Distinguish support for protein clearance from execution of protein catabolism. Reason: GBA1 perturbation changes protein accumulation and autophagic function, but its established catalytic step hydrolyses glycolipids. The inspected evidence does not resolve a direct protein-breakdown or protein-unfolding step performed by GBA1. Retain the regulatory and disease observations without promoting this broad electronic assertion to a direct catabolic role. |
| GO:0031175 neuron projection development | IMP NOT PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | KEEP AS NON CORE | Summary: Preserve the negative neurite-development comparison with its shared-genotype limitation. Reason: The reported neurite comparison involved Parkinson-disease-discordant twins sharing the heterozygous GBA1 allele, rather than a knockout versus wild-type experiment. Its null result is preserved as the incoming NOT context; it does not establish universal dispensability of GBA1 for neuronal development. Supporting Evidence: |
| GO:0032006 regulation of TOR signaling | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain experimentally grounded TOR modulation. Reason: The mouse donor and human-cell study link GCase deficiency to altered phospho-S6K, with recombinant-enzyme rescue in mouse fibroblasts. This is a secondary regulatory effect; the mechanism does not establish direct TOR-complex membership. Supporting Evidence: |
| GO:0032006 regulation of TOR signaling | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | KEEP AS NON CORE | Summary: GBA1 deficiency and rescue modulate a TOR-pathway readout. Reason: The original study measures phospho-S6K and related lysosomal endpoints. These support TOR regulation, with cell-specific rescue and proposed lipid mediation, rather than GBA1 acting as a kinase or a direct lysosome-reformation machine. Supporting Evidence: |
| GO:0032715 negative regulation of interleukin-6 production | IDA PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: Retain suppression of stimulus-induced IL-6 production. Reason: Human-cell GBA1 knockdown increases IL-6, and ceramide counteracts the response. The lipid-mediated effect is supported without assigning GBA1 transcription-factor activity. Supporting Evidence: |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain androgen-responsive enzyme output. Reason: In rat epidermal explants, DHT leaves GCase activity unchanged after one day but reduces it to 75% of control after two days. This delayed enzyme response does not establish hormone reception or direct signaling by GBA1; the selected external Results are distinguished from the cached abstract in the source guide. Supporting Evidence: |
| GO:0042176 regulation of protein catabolic process | IEA GO_REF:0000117 | TOO GENERAL | Summary: The general regulatory term is redundant with the retained lysosomal-specific claim. Reason: Official typed ancestry places regulation of lysosomal protein catabolic process under this term. Retaining that specific, independently supported regulatory assertion captures the relevant protein-clearance effect without a second generic process. |
| GO:0042391 regulation of membrane potential | IEA GO_REF:0000117 | MODIFY | Summary: Specify regulation of mitochondrial membrane potential. Reason: The mouse neuronal/astrocyte study directly measures reduced mitochondrial potential after Gba loss and altered ATP-synthase dependence. GO:0051881 is the verified is_a child matching this organelle-specific endpoint. This remains a secondary influence associated with quality-control and respiratory defects; it does not assign GBA1 an ion-channel, respiratory-chain or membrane-pump activity. Proposed replacements: regulation of mitochondrial membrane potential Supporting Evidence: |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000107 | ACCEPT | Summary: The lysosomal lumen contains the active GBA1 hydrolase. Reason: The donor has direct lumen localization evidence, and human GBA1 is a soluble secretory-pathway enzyme delivered to the lysosomal lumen. Peripheral membrane association on the lumenal side is compatible with this location; it is not a conflicting integral-membrane topology. |
| GO:0043202 lysosomal lumen | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: Retain the donor-grounded lysosomal-lumen location. Reason: The mouse-source study supports delivery into lysosomes, and independent human enzyme and receptor evidence agrees. This location identifies the side on which lipid hydrolysis occurs without assigning SCARB2 transport activity to GBA1. |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: Retain negative modulation of the p38 MAPK branch. Reason: The original perturbation and ceramide experiments support attenuation of p38 signaling; they do not show GBA1 directly dephosphorylating MAPK. Supporting Evidence: |
| GO:0043627 response to estrogen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain estrogen-responsive enzyme output. Reason: Rat explant activity increases after diethylstilbestrol; direct regulation versus maturation effects remains unresolved. Supporting Evidence: |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | KEEP AS NON CORE | Summary: GBA1 contributes a catalytic step to sphingosine salvage. Reason: GBA1 converts GlcCer to ceramide upstream of acid ceramidase, which releases sphingosine. Human-cell lipid tracing and knockdown support participation in this multistep route, not direct deacylation by GBA1. Supporting Evidence: |
| GO:0046513 ceramide biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: Ceramide is a direct product of GBA1-catalysed hydrolysis. Reason: The human-cell study supports ceramide formation through GlcCer breakdown and subsequent salvage. GBA1 performs the hydrolytic step; downstream reacylation belongs to ceramide synthases. |
| GO:0046527 glucosyltransferase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: Retain cholesterol transglucosylation. Reason: The authentic abstract reports recombinant-enzyme activity and human-cell rescue. Full Methods remain uninspected; net cellular direction is conditional. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity |
| GO:0046527 glucosyltransferase activity | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: GBA1 catalyses reversible glucose transfer between glucosylceramide and cholesterol. Reason: Selected original Methods and Results distinguish purified GBA1 from the separately expressed mouse GBA2 comparator and demonstrate both transfer directions. The secondary chemistry is real; its cellular direction depends on acceptor availability. No UDP-dependent glycosyltransferase reaction or GBA2-specific assay is assigned to GBA1. Supporting Evidence: |
| GO:0046527 glucosyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain secondary glucosyl transfer. Reason: GlcCer can donate glucose to a sterol; the term does not require UDP-glucose. Substrate availability controls reaction direction. |
| GO:0050295 steryl-beta-glucosidase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: Retain independently supported steryl-glucoside hydrolysis. Reason: The cited abstract emphasizes synthesis. Independent PMID:26724485 hydrolysis supports the claim without treating inaccessible assay details as a citation error. |
| GO:0050295 steryl-beta-glucosidase activity | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: Direct recombinant-enzyme assays support cholesteryl-glucoside hydrolysis. Reason: The original study reports recombinant GBA1 conversion of labelled GlcChol to cholesterol and distinguishes that hydrolysis from reversible transglucosylation. Its cellular inhibitor and lipid-accumulation results are complementary context. No claim is made that all sterol glycosides have identical turnover or that GBA1 transports cholesterol. Supporting Evidence: |
| GO:0050295 steryl-beta-glucosidase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: The RHEA mapping describes experimentally supported sterol-glucoside hydrolysis. Reason: The official GO definition and RHEA identifier specify cholesteryl glucoside hydrolysis to glucose and cholesterol. Independent GBA1 assays support that chemistry, including direct labelled-substrate turnover. It is a secondary substrate activity rather than the sole or defining lysosomal function. Supporting Evidence: |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: Retain the bounded anti-inflammatory cellular response. Reason: The human-cell study connects GBA1-dependent lipid metabolism to reduced pro-inflammatory IL-6 output. This supports the existing process without generalizing to every inflammatory setting. Supporting Evidence: |
| GO:0061436 establishment of skin barrier | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the tissue-specific catalytic contribution to epidermal barrier establishment. Reason: Rat GCase inhibition impairs extracellular lipid-lamella maturation and barrier formation while lamellar bodies and secretion remain substantially normal. This supports lipid processing that contributes directly to the barrier, not merely an unrelated downstream phenotype. It is a tissue-specific deployment of the core hydrolysis chemistry; the incoming human orthology transfer remains distinct from a human experiment. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Retain detection in the enriched urinary extracellular-vesicle preparation. Reason: The authentic supplemental table identifies P04062/GBA in pooled EPS-urine preparations. The main study used differential ultracentrifugation and duplicate analyses, and explicitly discusses soluble proteins and contaminants. Retain this non-core fraction-association evidence without claiming vesicle topology, biogenesis function, individual-donor replication or equivalence of the five natural products. Supporting Evidence: |
| GO:0071356 cellular response to tumor necrosis factor | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: Retain the functional response to TNF in human cells. Reason: GBA1 knockdown increases TNF-induced IL-6 in A549 cells. GBA1 contributes through lipid metabolism, without being a TNF receptor or signaling kinase. Supporting Evidence: |
| GO:0071548 response to dexamethasone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain glucocorticoid-responsive enzyme output. Reason: Rat dexamethasone treatment increases activity; the observation does not distinguish direct transcriptional regulation from maturation. Supporting Evidence: |
| GO:0097066 response to thyroid hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain thyroid-hormone-responsive enzyme output. Reason: Rat T3 treatment increases GCase activity without establishing GBA1 as a hormone receptor or transcriptional regulator. Supporting Evidence: |
| GO:0098773 skin epidermis development | IEA GO_REF:0000107 | TOO GENERAL | Summary: Barrier establishment captures the supported maturation role. Reason: GO:0061436 establishment of skin barrier is an explicitly verified is_a child of GO:0098773 skin epidermis development. The retained non-core barrier assertion captures the supported tissue maturation role, so the ancestor adds no distinct function. Supporting Evidence: |
| GO:1901805 beta-glucoside catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain beta-glucoside catabolism across the demonstrated substrate breadth. Reason: The authentic rat study directly measures synthetic beta-glucoside hydrolysis. Independent GBA1 assays extend this chemistry to bile-acid and sterol glucosides, beyond the retained GlcCer pathway. This does not imply equal turnover or physiological importance for every glucoside. |
| GO:1904457 positive regulation of neuronal action potential | IMP PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | UNDECIDED | Summary: The source-specific attribution of increased neuronal firing remains unresolved. Reason: The full main article is available; its relevant Results and Methods were read. Its inspected MEA comparison is between affected and unaffected twins sharing N370S; wild-type-versus-mutant biochemical comparisons and GBA1 rescue concern other endpoints. Those data do not isolate the effect of GBA1 on firing relative to wild type. This source-specific attribution remains UNDECIDED, without denying a conditional contribution; uninspected supplemental methods and figure pixels are separate access limits. Supporting Evidence: |
| GO:1905146 lysosomal protein catabolic process | IDA PMID:26392287 Glucocerebrosidase gene therapy prevents Ξ±-synucleinopathy o... | MARK AS OVER ANNOTATED | Summary: Separate lysosomal protein-clearance effects from a demonstrated protein-catabolic step. Reason: Human GBA1 transgene experiments in rodents reduce alpha-synuclein accumulation and protect neurons. Static LC3/p62 endpoints do not establish direct lysosomal protein turnover, and the authors leave induction versus blocked clearance unresolved. The positive results are retained, while assigning GBA1 itself the protein-catabolic process exceeds the demonstrated mechanism. The common has_input P37840 atom is projected from both original alternatives; their disjunctive locations remain intact in the evidence archive and are not represented by the flat projection. |
| GO:1905165 regulation of lysosomal protein catabolic process | TAS PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | KEEP AS NON CORE | Summary: Retain modulation of lysosomal protein clearance. Reason: The cited study reports reduced alpha-synuclein after GBA1 rescue and discusses impaired clearance; independent primary autophagic work supports a regulatory role. This is distinct from direct proteolysis by GBA1 and does not convert protein abundance into a measured degradation rate. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How does the genomic and transcript provenance of P04062-3 relate to the pseudogene cDNA in PMID:8294033, given the nine sequence differences from ENA BAA02546.1?
Q: Which endogenous products account for GBA1 activity in each tissue, and are the declared products 4 and 5 translated, delivered to lysosomes and catalytically active?
Q: Under which physiological substrate and compartment conditions does GBA1 cause net sterol-glycoside synthesis rather than hydrolysis, and how should that chemistry be placed under GO:0009247 given its narrow definition and broader typed children?
Q: Which lipid-dependent step connects GBA1 loss to altered autophagic flux and lysosome reformation, and can it be separated from downstream signaling and organelle dysfunction?
Q: Does changing GBA1 in isogenic dopamine neurons alter firing relative to wild-type controls, independently of twin-specific modifiers and alpha-synuclein or dopamine rescue endpoints?
Q: Under which physiological conditions does GBA1-dependent transfer from galactosylceramide to cholesterol contribute to galactosylcholesterol turnover, separately from GALC and GBA2 and from glucosylcholesterol metabolism?
Experiment: Use matched isogenic GBA1 genotypes and product-resolved rescue in differentiated dopamine neurons, measuring multielectrode-array activity together with enzyme activity, lipid substrates and alpha-synuclein turnover. Separate electrical rescue from protein-abundance or dopamine rescue.
Experiment: Compare the five sequence-verified products for endogenous translation, glycan processing, lysosomal delivery and natural lipid-substrate turnover, while independently establishing genomic origin for the disputed short-product transcript.
Experiment: Measure compartment-resolved glucosylcholesterol flux in matched GBA1 backgrounds while controlling glucosylceramide and cholesterol loading, then test whether selective changes in glucosylcholesterol turnover alter cellular disease phenotypes.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Which changes in GBA1-dependent glucosylcholesterol turnover causally contribute to Gaucher phenotypes, separately from glucosylceramide accumulation?
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Bidirectional GBA1 chemistry and substrate-dependent shifts are established. The original study supports net degradation under baseline conditions and formation with lysosomal cholesterol loading, while leaving disease consequences of altered glucosylcholesterol unresolved.
Significance: Lipid abundance changes do not establish which metabolite changes cause a cellular or disease phenotype.
What would resolve it: Perturb glucosylcholesterol turnover while controlling glucosylceramide burden in matched GBA1 backgrounds, and measure both compartmental lipid flux and disease-relevant cellular outcomes.
Provenance (the field's own admissions):
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)