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[1]. 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[2]. 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[3].
DNAJC6/Auxilin is a 910-amino acid protein with a distinctive domain structure:
Auxilin functions as a co-chaperone that specifically assists Hsc70 in clathrin uncoating:
Synaptic vesicles must be efficiently recycled to sustain neurotransmitter release during sustained activity. The clathrin-mediated endocytosis cycle consists of:
Auxilin is specifically required for the uncoating step, which is essential for vesicle fusion and recycling[11].
Auxilin is expressed predominantly in neurons, particularly in presynaptic terminals[12]. Its expression is highest in brain regions with high synaptic density, including the hippocampus, cortex, and basal ganglia[13]. The protein is essential for synaptic function, as demonstrated by the fact that auxilin knockout mice exhibit lethal neurological phenotypes[14].
Recessive loss-of-function mutations in DNAJC6 cause early-onset Parkinson's disease with the following characteristics:
The link between auxilin and PD highlights the importance of synaptic vesicle recycling in dopaminergic neuron survival.
Enhancing synaptic vesicle recycling represents a potential therapeutic strategy for Parkinson's disease:
Current research focuses on:
Complete auxilin knockout is embryonic lethal, indicating an essential role in development[18]. Conditional knockout in neurons leads to:
Zebrafish models of DNAJC6 deficiency show:
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Brautigam CA, et al. The ATPase cycle of the neuronal heat shock protein Hsc70. 2011. ↩︎
Edvardson S, et al. Auxilin deficiency causes early-onset Parkinson's disease. 2012. ↩︎
Hennessy F, et al. J-domain proteins. 2019. ↩︎
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Xing Y, et al. Structure of clathrin. 2020. ↩︎
Roth S, et al. Hsc70 in neuronal protein quality control. 2018. ↩︎
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McMahon HT, et al. Clathrin: a modular protein. 2021. ↩︎
Saheki Y, et al. Synaptic vesicle cycle. 2012. ↩︎
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Harris TW, et al. Auxilin expression in brain. 2019. ↩︎
Yim YI, et al. Auxilin is essential for development. 2010. ↩︎
Quadri M, et al. DNAJC6 mutations in early-onset Parkinson disease. 2016. ↩︎
Dehay B, et al. [Neurodegeneration in Parkinson's disease](https://doi.org/10.1016/S1474-4422(15). 2015. ↩︎
Scholz D, et al. Therapeutic approaches to Parkinson's disease. 2021. ↩︎
Tan J, et al. Auxilin knockout mice phenotypes. 2011. ↩︎
Kim D, et al. Neuron-specific auxilin deficiency. 2020. ↩︎
Song P, et al. Zebrafish model of DNAJC6 deficiency. 2019. ↩︎