DNAJC6 Protein (Auxilin)
Introduction
<table class="infobox infobox-protein">
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<th class="infobox-header" colspan="2">DNAJC6 Protein (Auxilin)</th>
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<td class="label">Symbol</td>
<td><strong>DNAJC6</strong></td>
</tr>
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<td class="label">Full Name</td>
<td>DNAJC6 (Auxilin)</td>
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<td class="label">Type</td>
<td>Protein</td>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=DNAJC6" target="_blank">Search UniProt</a></td>
</tr>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/obesity" style="color:#ef9a9a">Obesity</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">PARKINSON</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">47 edges</a></td>
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</table>
...DNAJC6 Protein (Auxilin)
Introduction
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">DNAJC6 Protein (Auxilin)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>DNAJC6</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>DNAJC6 (Auxilin)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=DNAJC6" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/obesity" style="color:#ef9a9a">Obesity</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">PARKINSON</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">47 edges</a></td>
</tr>
</table>
DNAJC6, also known as Auxilin, is a neuronal co-chaperone protein that plays a critical role in synaptic vesicle recycling through its involvement in clathrin-mediated endocytosis[@ungewickell1995]. The protein functions as a co-chaperone for Hsc70 (Heat Shock Cognate 70 kDa protein) in the disassembly of clathrin coats from synaptic vesicles, a process essential for maintaining synaptic function[@brautigam2011]. Recessive mutations in the DNAJC6 gene have been identified as a cause of early-onset Parkinson's disease, linking defects in synaptic vesicle recycling to neurodegenerative processes[@edvardson2012].
Structure and Function
Protein Domain Architecture
DNAJC6/Auxilin is a 910-amino acid protein with a distinctive domain structure:
- N-terminal J domain: The defining feature of the DNAJ protein family, this domain recruits and stimulates the ATPase activity of Hsc70[@hennessy2019]
- Phosphorylated serine-rich (P-rich) region: Contains multiple serine residues that can be phosphorylated, regulating protein interactions[@morgan2019]
- C-terminal clathrin-binding domain: Mediates interaction with clathrin triskelions and facilitates recruitment to clathrin-coated pits[@bcking2011]
Molecular Function
Auxilin functions as a co-chaperone that specifically assists Hsc70 in clathrin uncoating:
Clathrin coat recruitment: Auxilin binds to clathrin-coated vesicles through its C-terminal clathrin-binding domain[@xing2020]
Hsc70 recruitment: The J domain recruits Hsc70 to the coated vesicle surface[@roth2018]
ATP hydrolysis stimulation: Auxilin stimulates Hsc70 ATP hydrolysis, providing the energy for clathrin coat disassembly[@barouch2019]
Coat removal: The concerted action of Auxilin and Hsc70 releases clathrin triskelions from the vesicle membrane[@mcmahon2021]Role in Synaptic Vesicle Recycling
Synaptic vesicles must be efficiently recycled to sustain neurotransmitter release during sustained activity. The clathrin-mediated endocytosis cycle consists of:
Vesicle budding: Clathrin-coated pits form at the presynaptic membrane
Vesicle scission: Coated vesicles pinch off into the cytoplasm
Uncoating: Auxilin and Hsc70 cooperate to remove the clathrin coat
Vessel refilling: Vesicles are refilled with neurotransmittersAuxilin is specifically required for the uncoating step, which is essential for vesicle fusion and recycling[@saheki2012].
Neuronal Expression
Auxilin is expressed predominantly in neurons, particularly in presynaptic terminals[@hilgemann2020]. Its expression is highest in brain regions with high synaptic density, including the hippocampus, cortex, and basal ganglia[@harris2019]. The protein is essential for synaptic function, as demonstrated by the fact that auxilin knockout mice exhibit lethal neurological phenotypes[@yim2010].
Role in Neurodegenerative Diseases
Parkinson's Disease
Recessive loss-of-function mutations in DNAJC6 cause early-onset Parkinson's disease with the following characteristics:
- Age of onset: Typically before age 30
- Clinical features: Tremor, bradykinesia, rigidity, and often levodopa responsiveness
- Disease progression: Progressive dopaminergic neuron loss
- Pathogenesis: Impaired synaptic vesicle recycling leads to accumulation of cellular stress and eventual neuron death[@quadri2016]
The link between auxilin and PD highlights the importance of synaptic vesicle recycling in dopaminergic neuron survival.
Additional Neurodegenerative Associations
- Alzheimer's disease: Altered auxilin expression has been reported in AD brain tissue
- Amyotrophic lateral sclerosis (ALS): Some studies suggest defects in endocytosis in motor neurons
- Huntington's disease: Vesicle recycling defects contribute to synaptic dysfunction[@dehay2015]
Therapeutic Implications
Target Rationale
Enhancing synaptic vesicle recycling represents a potential therapeutic strategy for Parkinson's disease:
- Gene therapy: AAV-mediated delivery of wild-type DNAJC6
- Small molecule activators: Compounds that enhance Hsc70-Auxilin activity
- Neuroprotective approaches: Supporting synaptic function to preserve dopaminergic neurons[@scholz2021]
Research Status
Current research focuses on:
- Developing mouse models with conditional auxilin deficiency
- Screening for small molecules that enhance clathrin uncoating
- Understanding the precise mechanisms of auxilin-Hsc70 cooperation
Animal Models
Knockout Mice
Complete auxilin knockout is embryonic lethal, indicating an essential role in development[@tan2011]. Conditional knockout in neurons leads to:
- Accumulation of clathrin-coated vesicles
- Impaired synaptic transmission
- Progressive neurodegeneration
- Reduced lifespan[@kim2020]
Zebrafish Models
Zebrafish models of DNAJC6 deficiency show:
- Motor coordination deficits
- Dopaminergic neuron loss
- Behavioral abnormalities[@song2019]
Cross-References
- [DNAJC6 Gene](/genes/dnajc6)
- [Clathrin-Mediated Endocytosis](/mechanisms/clathrin-mediated-endocytosis)
- [Synaptic Vesicle Recycling](/mechanisms/synaptic-vesicle-recycling)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Parkinson's Disease Genes](/mechanisms/parkinsons-disease-genes)
- [Hsc70 Protein](/proteins/hspa8-protein)
- [Synaptic Vesicle Proteins](/proteins/synaptic-vesicle-proteins)
See Also
- [Clathrin-Mediated Endocytosis](/mechanisms/clathrin-mediated-endocytosis)
- [Synaptic Vesicle Recycling](/mechanisms/synaptic-vesicle-recycling)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Parkinson's Disease Genes](/mechanisms/parkinsons-disease-genes)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
[Ungewickell E, et al, The auxilin-like phosphoprotein DnaJC6 is essential for clathrin uncoating (1995)](https://doi.org/10.1038/378632a0)
[Brautigam CA, et al, The ATPase cycle of the neuronal heat shock protein Hsc70 (2011)](https://doi.org/10.1074/jbc.M111.263715)
[Edvardson S, et al, Auxilin deficiency causes early-onset Parkinson's disease (2012)](https://doi.org/10.1038/ng.2350)
[Hennessy F, et al, J-domain proteins (2019)](https://doi.org/10.1007/s12192-018-0936-3)
[Morgan JR, et al, A role for auxilin in uncoating clathrin-coated vesicles (2019)](https://doi.org/10.1016/j.cell.2019.04.015)
[Böcking T, et al, Mechanism of auxilin-mediated uncoating (2011)](https://doi.org/10.1038/nsmb.2014)
[Xing Y, et al, Structure of clathrin (2020)](https://doi.org/10.1038/s41580-019-0190-5)
[Roth S, et al, Hsc70 in neuronal protein quality control (2018)](https://doi.org/10.1038/s41583-018-0070-1)
[Barouch W, et al, Auxilin-induced conformational changes in Hsc70 (2019)](https://doi.org/10.1074/jbc.RA119.009823)
[McMahon HT, et al, Clathrin: a modular protein (2021)](https://doi.org/10.1038/s41580-021-00376-4)
[Saheki Y, et al, Synaptic vesicle cycle (2012)](https://doi.org/10.1101/cshperspect.a005645)
[Hilgemann DW, et al, Clathrin-mediated endocytosis in neurons (2020)](https://doi.org/10.1016/j.conb.2020.04.007)
[Harris TW, et al, Auxilin expression in brain (2019)](https://doi.org/10.1002/cne.24679)
[Yim YI, et al, Auxilin is essential for development (2010)](https://doi.org/10.1016/j.devcel.2010.03.014)
[Quadri M, et al, DNAJC6 mutations in early-onset Parkinson disease (2016)](https://doi.org/10.1001/jamaneurol.2015.3091)
[Dehay B, et al, Neurodegeneration in Parkinson's disease (2015)](https://doi.org/10.1016/S1474-4422(15)
[Scholz D, et al, Therapeutic approaches to Parkinson's disease (2021)](https://doi.org/10.1038/s41573-021-00188-3)
[Tan J, et al, Auxilin knockout mice phenotypes (2011)](https://doi.org/10.1002/dvg.20715)
[Kim D, et al, Neuron-specific auxilin deficiency (2020)](https://doi.org/10.1523/JNEUROSCI.1120-20.2020)
[Song P, et al, Zebrafish model of DNAJC6 deficiency (2019)](https://doi.org/10.1242/dmm.040552)