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The zebrafish gene dnajc6 (UniProt: A0A8M9QG43) encodes auxilin, a highly conserved neuronal co-chaperone protein that plays a critical role in clathrin-mediated endocytosis (CME), specifically in the uncoating step of synaptic vesicle recycling (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2). While zebrafish-specific functional studies are limited in the current literature, the fundamental molecular mechanisms of DNAJC6/auxilin are well-established across vertebrate model systems, enabling robust functional annotation based on evolutionary conservation.
The dnajc6 gene in zebrafish encodes auxilin, a member of the DnaJ/Hsp40 family of co-chaperone proteins (abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, karunanayake2021cytosolicproteinquality pages 1-2). The protein annotation from UniProt matches well with characterized auxilin proteins from other vertebrates, containing the essential domains: DnaJ domain (J_dom_sf, IPR036869), PTEN-like domain (Prot-tyrosine_phosphatase-like, IPR029021), C2 domain superfamily (C2_domain_sf, IPR035892; Tensin_C2-dom, IPR014020), and a clathrin-binding domain (jacquemyn2023parkinsonismmutationsin pages 1-2, abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3). The gene symbol "dnajc6" corresponds unambiguously to auxilin across vertebrate species, and the zebrafish ortholog shows high sequence conservation with mammalian DNAJC6, ensuring that functional insights from mammalian studies are applicable to zebrafish biology.
DNAJC6/auxilin functions as a J-domain protein (JDP) co-chaperone that partners with heat shock cognate 70 (HSC70/HSPA8) to catalyze the ATP-dependent disassembly of clathrin coats from newly formed clathrin-coated vesicles (CCVs) (abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, ng2024dysfunctionofsynaptic pages 2-3, karunanayake2021cytosolicproteinquality pages 1-2, banks2020hsc70amelioratesthe pages 1-2). The primary molecular function is not enzymatic in itself, but rather regulatory and targeting: auxilin recruits HSC70 to clathrin-coated structures and stimulates HSC70's ATPase activity through its conserved J-domain containing the essential His-Pro-Asp (HPD) motif (abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3, karunanayake2021cytosolicproteinquality pages 1-2).
The mechanism proceeds as follows:
1. Substrate recognition: Auxilin binds to assembled clathrin lattices on newly internalized vesicles via its clathrin-binding domain (CBD) (jacquemyn2023parkinsonismmutationsin pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2).
2. Membrane targeting: The PTEN-like domain binds phosphoinositides, particularly PI(4,5)P2 and its dephosphorylated products, helping to target auxilin to endocytic membranes (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3).
3. HSC70 recruitment and activation: The J-domain of auxilin interacts with the nucleotide-binding domain of HSC70, stimulating ATP hydrolysis (karunanayake2021cytosolicproteinquality pages 1-2, banks2020hsc70amelioratesthe pages 1-2).
4. Clathrin disassembly: ATP-bound HSC70 binds to clathrin triskelions, and the energy from ATP hydrolysis causes conformational changes that destabilize the clathrin lattice, leading to coat disassembly and release of clathrin into the cytosol (kaci2026clathrinmediatedendocytosisas pages 1-2, ng2024dysfunctionofsynaptic pages 2-3, karunanayake2021cytosolicproteinquality pages 1-2, banks2020hsc70amelioratesthe pages 1-2).
The primary substrate of the auxilin-HSC70 complex is clathrin heavy chain assembled into polyhedral lattices (clathrin cages) on coated vesicles (abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, karunanayake2021cytosolicproteinquality pages 1-2, banks2020hsc70amelioratesthe pages 1-2). Auxilin does not directly act as a protease or enzyme; rather, it functions as a targeting and activating co-factor that directs HSC70 chaperone activity specifically toward clathrin disassembly (karunanayake2021cytosolicproteinquality pages 1-2, banks2020hsc70amelioratesthe pages 1-2). This substrate specificity is conferred by the clathrin-binding domain of auxilin, which recognizes assembled clathrin structures, and the PTEN-like domain, which senses the phosphoinositide composition of vesicle membranes (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3).
DNAJC6/auxilin is predominantly localized to presynaptic nerve terminals in neurons, where it concentrates in peri-active zone regions adjacent to active zones—the specialized sites where synaptic vesicle endocytosis occurs (abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3). Immunofluorescence and biochemical studies demonstrate that auxilin colocalizes with other endocytic machinery proteins including dynamin, and is enriched at clathrin-coated pits and newly formed clathrin-coated vesicles (abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3). The protein carries out its function at the plasma membrane-cytoplasm interface during the final stages of clathrin-mediated endocytosis (abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, imoto2025beyondclathrindecoding pages 1-3).
DNAJC6 is predominantly expressed in neurons, particularly dopaminergic neurons in the substantia nigra and striatum (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5). Recent studies have also identified significant expression in oligodendrocytes (abela2024neurodevelopmentalandsynaptic pages 1-2) and, unexpectedly, in astrocytes, where DNAJC6 appears to play roles in phagocytic function, autolysosomal clearance, and mitochondrial homeostasis (darsono2026dysregulationofastrocytic pages 1-5). The enrichment of auxilin in neurons reflects its critical role in the high-frequency synaptic vesicle recycling required for neurotransmission (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2).
Auxilin functions at the terminal uncoating step of CME, which is essential for synaptic vesicle recycling (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, ng2024dysfunctionofsynaptic pages 2-3). CME proceeds through several stages: cargo recognition, clathrin coat assembly, membrane invagination, dynamin-mediated fission, and finally coat disassembly (kaci2026clathrinmediatedendocytosisas pages 1-2, imoto2025beyondclathrindecoding pages 1-3). Auxilin acts after vesicle scission to remove the clathrin coat, thereby regenerating free clathrin for subsequent rounds of endocytosis and releasing nascent synaptic vesicles for refilling with neurotransmitters (abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, ng2024dysfunctionofsynaptic pages 2-3).
Recent comprehensive reviews position CME as a central axis for Parkinson's disease etiopathogenesis, with auxilin (DNAJC6) being one of the key regulatory proteins genetically linked to parkinsonism (kaci2026clathrinmediatedendocytosisas pages 1-2). The 2024-2026 literature highlights that defects in auxilin-mediated uncoating lead to accumulation of clathrin-coated vesicles, depletion of synaptic vesicle pools, and impaired neurotransmission (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2, ng2024dysfunctionofsynaptic pages 2-3).
At synapses, auxilin is essential for maintaining the readily releasable pool and recycling pool of synaptic vesicles (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2). Following neurotransmitter release via exocytosis, synaptic vesicle membrane components must be retrieved and recycled to sustain ongoing neurotransmission. Auxilin-mediated clathrin uncoating is rate-limiting for this process, particularly under conditions of sustained or high-frequency stimulation (cheng2023impairedpresynapticplasticity pages 1-2, ng2024dysfunctionofsynaptic pages 2-3).
Loss of auxilin function in mouse models results in:
- Accumulation of clathrin-coated vesicles and empty clathrin cages at presynaptic terminals (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2, chiu2024downregulationofprotease pages 1-2)
- Depletion of synaptic vesicles available for release (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2)
- Impaired presynaptic short-term plasticity, including reduced facilitation and depression (cheng2023impairedpresynapticplasticity pages 1-2)
- Defective visual and circuit responses in cortical neurons (cheng2023impairedpresynapticplasticity pages 1-2)
These findings demonstrate that auxilin function is critical for both basal synaptic transmission and adaptive synaptic plasticity (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2).
Auxilin function is intimately coordinated with phosphoinositide metabolism during endocytosis (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3). The lipid phosphatase synaptojanin-1 (SYNJ1, also a Parkinson's disease gene, PARK20) dephosphorylates PI(4,5)P2 on newly formed vesicles, triggering dissociation of clathrin adaptors (ng2024dysfunctionofsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 2-3). Auxilin's PTEN-like domain binds to phosphoinositides, and the temporal coordination of PI(4,5)P2 dephosphorylation and auxilin/HSC70-mediated clathrin uncoating is essential for efficient vesicle recycling (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3).
Pathogenic DNAJC6 mutations in Drosophila models cause specific alterations in membrane lipid composition, particularly reductions in long-chain polyunsaturated fatty acid-containing lipids and phosphatidylinositol species critical for synaptic vesicle recycling (jacquemyn2023parkinsonismmutationsin pages 1-2). Remarkably, overexpression of synaptojanin-1 rescues these lipid defects as well as neurological phenotypes and neurodegeneration in DNAJC6 mutants, revealing a functional relationship between these two Parkinson's disease-linked proteins (jacquemyn2023parkinsonismmutationsin pages 1-2).
Beyond its canonical role in synaptic vesicle recycling, recent studies reveal that DNAJC6 dysfunction impacts the endolysosomal pathway and autophagy (ng2024dysfunctionofsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3). DNAJC6 deficiency in cellular models leads to:
- Reduced lysosome number and impaired lysosomal function (chiu2024downregulationofprotease pages 1-2)
- Downregulation of lysosomal protease cathepsin D (chiu2024downregulationofprotease pages 1-2)
- Impaired macroautophagy and accumulation of toxic proteins, particularly pathologic α-synuclein and phospho-α-synuclein (ng2024dysfunctionofsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2)
- ER stress and mitochondrial dysfunction (chiu2024downregulationofprotease pages 1-2)
These findings suggest that auxilin's role extends beyond the plasma membrane to encompass broader vesicular trafficking and protein quality control pathways (chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3). The connection to endolysosomal dysfunction may explain why DNAJC6 is increasingly recognized as a contributor not only to familial Parkinson's disease but also to sporadic disease pathogenesis (darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3).
The functional domains of DNAJC6/auxilin and their roles are summarized below:
| Domain Name | Function | Key Features | Role in Disease |
|---|---|---|---|
| J-domain (C-terminal DnaJ domain) | Recruits and activates HSC70/HSPA8 to drive ATP-dependent disassembly of clathrin coats from newly formed clathrin-coated vesicles; this is the core catalytic co-chaperone step in auxilin-mediated uncoating. | Conserved DnaJ/Hsp40-family J-domain with essential HPD motif; stimulates HSC70 ATPase activity; pathogenic human R927G mutation lies in this region and impairs the HSC70-coupled uncoating function; Drosophila homolog R1119G models the same defect (jacquemyn2023parkinsonismmutationsin pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3, chiu2024downregulationofprotease pages 1-2) | Strongly implicated in PARK19. Missense mutation R927G and truncating alleles that remove or disrupt the C-terminal region impair clathrin uncoating, causing synaptic vesicle recycling defects, synaptic dysfunction, and juvenile/early-onset parkinsonism (jacquemyn2023parkinsonismmutationsin pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, chiu2024downregulationofprotease pages 1-2) |
| PTEN-like domain | Binds phosphoinositide-containing membranes and helps target auxilin to endocytic intermediates during clathrin-mediated endocytosis, coupling membrane lipid state to uncoating. | PTEN-like region is not described as a catalytic lipid phosphatase here; instead it contains a motif for mono-phosphoinositide binding and is proposed to promote membrane recruitment during CME, functionally linking auxilin to PI(4,5)P2/Synaptojanin-regulated membrane remodeling (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) | Disease-associated mutations that truncate auxilin upstream of the J-domain likely also remove or destabilize this membrane-targeting region, reducing productive recruitment to coated vesicles and worsening endocytic failure in PARK19 (jacquemyn2023parkinsonismmutationsin pages 1-2, chiu2024downregulationofprotease pages 1-2) |
| C2 domain / Tensin-type C2 region | Likely contributes to membrane association and spatial positioning of auxilin at endocytic membranes, supporting access to clathrin-coated vesicles at presynaptic terminals. | UniProt/domain annotation identifies a C2-domain superfamily/Tensin_C2-like module; C2 domains commonly mediate phospholipid-dependent membrane interactions. Although not deeply dissected in the retrieved papers, the annotated architecture is consistent with synaptic membrane localization during CME (abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3) | No domain-specific zebrafish or human pathogenic variant was directly functionally resolved in the retrieved recent literature, but disruption of N-terminal targeting architecture would be expected to impair presynaptic localization and thereby clathrin uncoating efficiency (abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3) |
| Clathrin-binding domain (CBD) | Binds clathrin cages/coated vesicles and positions auxilin on the clathrin lattice so the J-domain can recruit HSC70 for uncoating. | Located between the PTEN-like region and J-domain in auxilin domain maps; directly linked to the final stage of CME, where auxilin binds engulfed clathrin-coated vesicles before coat removal; works together with membrane-binding regions and the J-domain to couple vesicle recognition to uncoating (jacquemyn2023parkinsonismmutationsin pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2) | Truncating PARK19 mutations such as Q789X/Q846X are expected to abolish or severely compromise this region and downstream uncoating machinery, leading to accumulation of clathrin-coated vesicles, depletion of synaptic vesicles, and dopaminergic vulnerability (jacquemyn2023parkinsonismmutationsin pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2, chiu2024downregulationofprotease pages 1-2) |
Table: This table summarizes the major annotated domains of DNAJC6/auxilin and how each contributes to clathrin uncoating during synaptic vesicle recycling. It also links specific domains and mutations to PARK19 pathogenesis, which is useful for interpreting functional annotation of zebrafish dnajc6.
This multi-domain architecture enables auxilin to integrate multiple signals—clathrin lattice recognition, membrane phosphoinositide status, and HSC70 chaperone recruitment—to execute precise temporal and spatial control over clathrin uncoating (jacquemyn2023parkinsonismmutationsin pages 1-2, abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3, karunanayake2021cytosolicproteinquality pages 1-2).
The table below summarizes the key cellular pathways and processes involving DNAJC6/auxilin:
| Pathway/Process | Auxilin's Specific Role | Key Interacting Proteins | Functional Consequences of Deficiency |
|---|---|---|---|
| Clathrin-mediated endocytosis (CME) | Auxilin/DNAJC6 acts at the terminal uncoating step of CME by binding clathrin-coated vesicles and recruiting HSC70 through its J-domain to stimulate HSC70 ATPase activity and disassemble the clathrin coat; membrane recruitment is coordinated with phosphoinositide state during vesicle maturation (abela2024neurodevelopmentalandsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) | HSC70/HSPA8, clathrin heavy chain, AP-2/adaptor machinery, dynamin, synaptojanin-1 (kaci2026clathrinmediatedendocytosisas pages 1-2, ng2024dysfunctionofsynaptic pages 2-3, chiu2024downregulationofprotease pages 1-2) | Accumulation of clathrin-coated vesicles and empty clathrin cages, slower or failed uncoating, impaired endocytic membrane trafficking, and reduced cytosolic clathrin homeostasis in dopaminergic neurons (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2, chiu2024downregulationofprotease pages 1-2) |
| Synaptic vesicle recycling | At presynaptic peri-active zones, auxilin regenerates synaptic vesicles from newly formed coated vesicles, helping maintain vesicle availability for repeated neurotransmission and preserving the readily releasable/recycling pools (abela2024neurodevelopmentalandsynaptic pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3, cheng2023impairedpresynapticplasticity pages 1-2) | HSC70, clathrin, dynamin, synaptojanin-1, endophilin-associated endocytic machinery (jacquemyn2023parkinsonismmutationsin pages 2-3, cheng2023impairedpresynapticplasticity pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) | Disturbed synaptic vesicle recycling and homeostasis, depletion or abnormal refilling of releasable vesicle pools, impaired presynaptic short-term plasticity, altered visual/circuit responses, and synaptic dysfunction preceding neurodegeneration (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) |
| Endolysosomal pathway | Recent work places DNAJC6 beyond synaptic uncoating, linking it to endolysosomal maintenance and vesicular trafficking in neurons and glia; auxilin dysfunction appears to compromise lysosome-associated trafficking and degradative capacity (darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3) | LRRK2-regulated pathways, α-synuclein-linked vesicular networks, lysosomal proteases including cathepsin D (chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3) | Reduced lysosome number, defective endolysosomal clearance, buildup of toxic proteins/organelles, enhanced neuronal stress, and contribution to dopaminergic degeneration and sporadic PD-associated pathology (chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3) |
| Phosphoinositide metabolism | Auxilin function is coordinated with phosphoinositide remodeling during endocytosis; after synaptojanin-1 dephosphorylates PI(4,5)P2, auxilin/HSC70 recruitment promotes coat removal. Auxilin also contains a PTEN-like phosphoinositide-binding region that likely helps target it to vesicle membranes (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) | Synaptojanin-1/SYNJ1, PI(4,5)P2, clathrin adaptors, HSC70 (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) | Failure to couple lipid remodeling to coat removal, persistence of endocytic intermediates, defective vesicle recycling, and strong functional synergy with SYNJ1-related Parkinsonism pathways (jacquemyn2023parkinsonismmutationsin pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 2-3) |
| Lipid homeostasis | Pathogenic DNAJC6 mutations alter neuronal membrane lipid composition, especially long-chain polyunsaturated fatty acid-containing lipids and phosphatidylinositol species important for synaptic vesicle recycling and organelle function (jacquemyn2023parkinsonismmutationsin pages 1-2) | Synaptojanin-1, phosphatidylinositol lipid species, long-chain PUFA-containing membrane lipids (jacquemyn2023parkinsonismmutationsin pages 1-2) | Lipid imbalance, synaptic dysfunction, neurological defects, and neurodegeneration; in Drosophila, Synj1 overexpression rescues lipid defects and neuronal phenotypes, supporting functional coupling between auxilin and phosphoinositide/lipid metabolism (jacquemyn2023parkinsonismmutationsin pages 1-2) |
| Autophagy / autolysosomal clearance | Auxilin deficiency has emerging downstream effects on autophagy, likely secondary to disrupted vesicle trafficking and lysosomal homeostasis; recent studies link DNAJC6 loss to impaired autolysosomal and macroautophagic function in neurons and astrocytes (ng2024dysfunctionofsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5) | Cathepsin D, α-synuclein, lysosomes, LRRK2-associated regulatory pathways (chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5) | Impaired macroautophagy, accumulation of pathologic α-synuclein/phospho-α-synuclein, ER stress, mitochondrial dysfunction, inflammatory astrocyte phenotypes, and enhanced neurodegeneration (chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5) |
Table: This table summarizes the principal cellular pathways involving DNAJC6/auxilin and highlights its mechanistic roles, interacting proteins, and the functional consequences of loss or mutation. It is useful for functional annotation because it connects the protein's core synaptic uncoating function to broader endolysosomal, lipid, and autophagic phenotypes reported in recent literature.
These pathway connections demonstrate that auxilin is not simply a clathrin uncoating factor, but a central node linking membrane trafficking, lipid metabolism, and protein homeostasis in neurons and glia (jacquemyn2023parkinsonismmutationsin pages 1-2, abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5).
Biallelic loss-of-function mutations in human DNAJC6 cause PARK19, a form of autosomal recessive juvenile-onset Parkinson's disease characterized by rapidly progressive parkinsonism-dystonia in childhood, often with additional neurodevelopmental features including intellectual disability, seizures, and neuropsychiatric symptoms (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, kaci2026clathrinmediatedendocytosisas pages 1-2, chiu2024downregulationofprotease pages 1-2). Common pathogenic mutations include:
- R927G (missense mutation in the J-domain HPD motif) (jacquemyn2023parkinsonismmutationsin pages 1-2, abela2024neurodevelopmentalandsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2)
- Q789X, Q846X (nonsense truncating mutations) (jacquemyn2023parkinsonismmutationsin pages 1-2, chiu2024downregulationofprotease pages 1-2)
These mutations result in auxilin deficiency and impaired clathrin uncoating, leading to accumulation of clathrin-coated vesicles, synaptic vesicle depletion, and selective vulnerability of dopaminergic neurons (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, chiu2024downregulationofprotease pages 1-2).
A landmark 2024 study demonstrated that lentiviral-mediated DNAJC6 gene transfer rescues clathrin-mediated endocytosis defects in human iPSC-derived midbrain dopaminergic neurons from PARK19 patients, providing proof-of-concept for gene therapy as a disease-modifying strategy (abela2024neurodevelopmentalandsynaptic pages 1-2). This work, published in Brain (https://doi.org/10.1093/brain/awae020), represents a significant advance in precision medicine for DNAJC6-associated parkinsonism.
Emerging evidence from 2026 indicates that DNAJC6 dysregulation is not limited to familial PARK19 but also contributes to sporadic Parkinson's disease pathogenesis (darsono2026dysregulationofastrocytic pages 1-5). A study published in the Journal of Clinical Investigation (https://doi.org/10.1172/jci194989) found that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues from late-onset sporadic PD patients compared to age-matched controls (darsono2026dysregulationofastrocytic pages 1-5). Mechanisms underlying this downregulation include impaired transcription mediated by midbrain-specific factors (NURR1, FOXA2) and reduced protein stability regulated by LRRK2 (darsono2026dysregulationofastrocytic pages 1-5).
A surprising recent finding is that DNAJC6 is robustly expressed in astrocytes, and astrocytic DNAJC6 deficiency contributes to PD pathogenesis through non-cell-autonomous mechanisms (darsono2026dysregulationofastrocytic pages 1-5). Astrocytic DNAJC6 loss impairs phagocytic clearance, autolysosomal function, and mitochondrial homeostasis, while promoting a pro-inflammatory phenotype that exacerbates dopaminergic neurodegeneration (darsono2026dysregulationofastrocytic pages 1-5). Importantly, CRISPRa-mediated epigenetic restoration of DNAJC6 expression in both neurons and astrocytes in an α-synuclein-induced mouse model of PD alleviated behavioral deficits and neuropathology, suggesting that targeting both neuronal and glial DNAJC6 could represent a therapeutic strategy (darsono2026dysregulationofastrocytic pages 1-5).
A 2026 review in npj Parkinson's Disease (https://doi.org/10.1038/s41531-025-01162-1) highlights emerging roles for oligodendrocytes in DNAJC6 Parkinson's disease, emphasizing that auxilin is involved not only in synaptic vesicle recycling but also in broader endolysosomal dysfunction affecting multiple cell types in the brain (abela2024neurodevelopmentalandsynaptic pages 1-2).
Auxilin knockout mice exhibit:
- Accumulation of clathrin-coated vesicles and empty clathrin cages at presynaptic terminals (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2, chiu2024downregulationofprotease pages 1-2)
- Synaptic vesicle depletion and impaired vesicle recycling (abela2024neurodevelopmentalandsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2)
- Presynaptic plasticity defects, including reduced short-term facilitation and depression (cheng2023impairedpresynapticplasticity pages 1-2)
- Impaired visual cortical responses and optokinetic reflexes (cheng2023impairedpresynapticplasticity pages 1-2)
- Progressive dopaminergic neuron loss (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2)
- Motor deficits consistent with parkinsonism (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2)
Drosophila knock-in models carrying the pathogenic R1119G mutation (homologous to human R927G) recapitulate:
- Lipid metabolism defects, particularly reductions in long-chain polyunsaturated fatty acid-containing membrane lipids and phosphatidylinositol species (jacquemyn2023parkinsonismmutationsin pages 1-2)
- Synaptic dysfunction and abnormal vesicle size distribution (jacquemyn2023parkinsonismmutationsin pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3)
- Neurodegeneration and reduced longevity (jacquemyn2023parkinsonismmutationsin pages 1-2, jacquemyn2023parkinsonismmutationsin pages 2-3)
- Behavioral/motor deficits (jacquemyn2023parkinsonismmutationsin pages 1-2)
Patient-derived induced pluripotent stem cells differentiated into midbrain dopaminergic neurons show:
- Auxilin deficiency (abela2024neurodevelopmentalandsynaptic pages 1-2)
- Impaired clathrin-mediated endocytosis assessed by FM1-43 uptake assays (abela2024neurodevelopmentalandsynaptic pages 1-2)
- Disturbed synaptic vesicle recycling and homeostasis (abela2024neurodevelopmentalandsynaptic pages 1-2)
- Neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation (abela2024neurodevelopmentalandsynaptic pages 1-2)
While zebrafish are mentioned as an attractive model for studying Parkinson's disease genes due to conserved neurobiochemical mechanisms and well-characterized neuronal circuitry (abela2024neurodevelopmentalandsynaptic pages 1-2), specific functional studies of dnajc6 in zebrafish are limited in the current literature. Zebrafish dnajc6 would be expected to function similarly to mammalian orthologs based on high sequence conservation and shared domain architecture. Zebrafish could be valuable for studying developmental and early neurodegenerative phenotypes associated with dnajc6 loss of function, as well as for chemical screens to identify therapeutic compounds.
Leading researchers in the field emphasize that clathrin-mediated endocytosis has emerged as a central axis for Parkinson's disease etiopathogenesis (kaci2026clathrinmediatedendocytosisas pages 1-2). A 2026 Perspective in Journal of Cell Science (https://doi.org/10.1242/jcs.264368) by Kaci et al. states: "Emerging data from both Mendelian and idiopathic forms of Parkinson's disease and parkinsonism syndromes supports a role for key players in CME in determining the risk of developing these neurodegenerative disorders" (kaci2026clathrinmediatedendocytosisas pages 1-2).
A comprehensive 2024 review by Ng & Cao in Neural Regeneration Research (https://doi.org/10.4103/nrr.nrr-d-23-01624) emphasizes the "dying back" mechanism in PD, whereby synaptic dysfunction and impaired synaptic vesicle recycling represent early features of disease, followed by axonal degeneration and eventual loss of dopamine cell bodies in the midbrain (ng2024dysfunctionofsynaptic pages 1-2). The authors note that "several genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway" and that "impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease" (ng2024dysfunctionofsynaptic pages 1-2).
Current understanding positions auxilin at the intersection of multiple pathogenic processes:
1. Primary synaptic dysfunction through defective vesicle recycling (abela2024neurodevelopmentalandsynaptic pages 1-2, ng2024dysfunctionofsynaptic pages 1-2, cheng2023impairedpresynapticplasticity pages 1-2)
2. Endolysosomal impairment affecting autophagy and protein clearance (chiu2024downregulationofprotease pages 1-2, darsono2026dysregulationofastrocytic pages 1-5, yahya2023geneticevidencefor pages 1-3)
3. Lipid metabolism dysregulation impacting membrane homeostasis (jacquemyn2023parkinsonismmutationsin pages 1-2)
4. Non-cell-autonomous pathology involving astrocytes and oligodendrocytes (abela2024neurodevelopmentalandsynaptic pages 1-2, darsono2026dysregulationofastrocytic pages 1-5)
The zebrafish dnajc6 gene encodes auxilin, a J-domain protein co-chaperone that functions as a critical regulator of clathrin-mediated endocytosis. The primary molecular function of auxilin is to recruit and activate HSC70 chaperone to catalyze ATP-dependent disassembly of clathrin coats from newly formed vesicles at presynaptic terminals. This uncoating step is essential for synaptic vesicle recycling, maintenance of neurotransmitter release capacity, and neuronal survival.
Auxilin localizes to peri-active zones at synapses where it operates at the plasma membrane-cytoplasm interface during endocytosis. The protein is predominantly expressed in neurons (especially dopaminergic neurons) and also in oligodendrocytes and astrocytes. Loss of auxilin function causes accumulation of clathrin-coated vesicles, depletion of synaptic vesicles, impaired synaptic transmission, and progressive neurodegeneration.
Beyond its canonical synaptic role, auxilin participates in broader cellular pathways including endolysosomal trafficking, autophagy, phosphoinositide metabolism, and lipid homeostasis. These interconnected functions explain why DNAJC6 mutations cause not only juvenile-onset Parkinson's disease (PARK19) but also why DNAJC6 dysregulation contributes to sporadic Parkinson's disease pathogenesis.
Recent advances (2023-2026) demonstrate the therapeutic potential of DNAJC6 restoration through gene therapy, the importance of glial DNAJC6 in disease pathogenesis, and the mechanistic links between clathrin uncoating defects and broader neurodegenerative processes. While zebrafish-specific functional studies of dnajc6 are currently limited, the high evolutionary conservation of auxilin structure and function across vertebrates provides a strong foundation for functional annotation and future experimental investigations in the zebrafish model.
All citations are provided inline throughout this report using the format () as specified. Key publications include:
Report Completed: This comprehensive functional annotation integrates findings from recent authoritative literature (2023-2026) with established knowledge to provide a detailed understanding of dnajc6/auxilin function applicable to zebrafish biology.
References
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