DNAJC6 (DnaJ Heat Shock Protein Family Member C6), also known as Auxilin-1, is a neuronal co-chaperone specifically involved in [clathrin-mediated endocytosis](/mechanisms/clathrin-mediated-endocytosis). Auxilin recognizes [clathrin](/proteins/clathrin-heavy-chain)-coated vesicles and recruits [Hsc70](/proteins/hsc70-protein) to facilitate clathrin cage disassembly. It contains a J-domain for Hsc70 interaction and a phosphoinositide-binding domain for membrane association. Beyond endocytosis, auxilin is critically involved in [synaptic vesicle recycling](/mechanisms/synaptic-vesicle-recycling) and neuronal signaling.
DNAJC6 is one of the few genes where recessive loss-of-function mutations cause early-onset [Parkinson's disease](/diseases/parkinsons-disease), highlighting the importance of endocytic trafficking in dopaminergic neuron survival.
Function
Clathrin-Mediated Endocytosis
DNAJC6 encodes auxilin-1, a neuronal co-chaperone specifically involved in clathrin-mediated endocytosis. The protein performs several critical functions:
Clathrin recognition: Auxilin specifically binds to clathrin-coated vesicles via its clathrin-binding domain
Hsc70 recruitment: The J-domain recruits Hsc70 (heat shock cognate 70 kDa protein) to the coated vesicle
ATP-dependent disassembly: Hsc70, powered by ATP hydrolysis, disassembles the clathrin lattice
Membrane association: The phosphoinositide-binding domain targets auxilin to membrane regions where endocytosis occurs
Synaptic Vesicle Recycling
In presynaptic terminals, auxilin is essential for:
Rapid recycling of synaptic vesicles after neurotransmitter release
Maintaining the pool of readily releasable vesicles
Supporting high-frequency synaptic transmission
Protein-Protein Interactions
| Partner | Interaction Type | Function | |---------|-----------------|----------| | [Clathrin](/proteins/clathrin-heavy-chain) | Direct binding | Clathrin coat component | | [Hsc70](/proteins/hsc70-protein) | J-domain mediated | Chaperone for disassembly | | [Cyclin G-associated kinase (GAK)](https://www.uniprot.org/Q9UQF0) | Synergistic | Auxilin-like function in non-neuronal cells | | [Dynamin](/proteins/dynamin-1) | Functional | Membrane fission during endocytosis |
Disease Associations
Parkinson's Disease
| Aspect | Details | |--------|---------| | Inheritance | Autosomal recessive | | Onset | Early-onset (typically before age 40) | | Phenotype | Progressive parkinsonism with good levodopa response | | Mechanism | Loss of auxilin function → impaired endocytosis → synaptic vesicle recycling deficits → dopaminergic neuron degeneration | | Pathology | Loss of dopaminergic neurons in [substantia nigra pars compacta](/brain-regions/substantia-nigra) |
Early-Onset Parkinsonism
DNAJC6 mutations lead to synaptic vesicle recycling deficits and dopaminergic neuron degeneration. Patients typically present with:
Tremor and bradykinesia
Good response to levodopa
May develop dyskinesias
Disease progression over decades
Model Systems
Studies in:
Knockout mice: Show synaptic vesicle recycling defects
Zebrafish: Model recapitulates dopaminergic neuron loss
Induced neurons (iPSCs): Patient-derived neurons show endocytic deficits
Expression Pattern
DNAJC6 is expressed almost exclusively in the brain, with highest expression in: