DNAJC6 Protein (Auxilin)

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DNAJC6 Protein (Auxilin)

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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 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

The Clathrin-Mediated Endocytosis Cycle

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 neurotransmitters

Auxilin 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)

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)

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Related Entities

DNAJC6PROTEIN

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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

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Incoming

9

Outgoing

10

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

DNAJC6 Protein (Auxilin)

DNAJC6 Protein (Auxilin)

Introduction

DNAJC6 Protein (Auxilin)

Introduction

Structure and Function

Protein Domain Architecture

Molecular Function

Role in Synaptic Vesicle Recycling

The Clathrin-Mediated Endocytosis Cycle

Neuronal Expression

Role in Neurodegenerative Diseases

Parkinson's Disease

Additional Neurodegenerative Associations

Therapeutic Implications

Target Rationale

Research Status

Animal Models

Knockout Mice

Zebrafish Models

Cross-References

See Also

External Links

References

💬 Discussion