DNAJC6 — DnaJ Heat Shock Protein Family (Hsp40) Member C6
Introduction
flowchart TD
DNAJC6["DNAJC6"] -->|"interacts with"| FBXO7["FBXO7"]
DNAJC6["DNAJC6"] -->|"interacts with"| PINK1["PINK1"]
DNAJC6["DNAJC6"] -->|"interacts with"| PRKN["PRKN"]
DNAJC6["DNAJC6"] -->|"interacts with"| SYNJ1["SYNJ1"]
DNAJC6["DNAJC6"] -->|"interacts with"| VPS13C["VPS13C"]
DNAJC6["DNAJC6"] -->|"interacts with"| GBA1["GBA1"]
DNAJC6["DNAJC6"] -->|"interacts with"| LRRK2["LRRK2"]
DNAJC6["DNAJC6"] -->|"interacts with"| PARK7["PARK7"]
DNAJC6["DNAJC6"] -->|"interacts with"| SNCA["SNCA"]
DNAJC6["DNAJC6"] -->|"expressed in"| neurons["neurons"]
DNAJC6["DNAJC6"] -->|"regulates"| Obesity["Obesity"]
DNAJC6["DNAJC6"] -->|"inhibits"| Ms["Ms"]
DNAJC6["DNAJC6"] -->|"associated with"| Parkinson["Parkinson"]
DNAJC6["DNAJC6"] -->|"associated with"| Als["Als"]
style DNAJC6 fill:#4fc3f7,stroke:#333,color:#000
DNAJC6 (DnaJ Heat Shock Protein Family Member C6), also known as auxilin-2, is a neuronal-specific co-chaperone protein that plays essential roles in synaptic vesicle recycling and lysosomal function. Located on chromosome 19q13.43, this gene encodes a protein primarily expressed in [neurons](/entities/neurons) throughout the brain, with particularly high levels in the substantia nigra, basal ganglia, and cerebral [cortex](/brain-regions/cortex)[@edvardson2012].
...DNAJC6 — DnaJ Heat Shock Protein Family (Hsp40) Member C6
Introduction
Mermaid diagram (expand to render)
DNAJC6 (DnaJ Heat Shock Protein Family Member C6), also known as auxilin-2, is a neuronal-specific co-chaperone protein that plays essential roles in synaptic vesicle recycling and lysosomal function. Located on chromosome 19q13.43, this gene encodes a protein primarily expressed in [neurons](/entities/neurons) throughout the brain, with particularly high levels in the substantia nigra, basal ganglia, and cerebral [cortex](/brain-regions/cortex)[@edvardson2012].
DNAJC6 is distinct from its relative DNAJC5 (cystinosin) in that it is neuron-specific and functions in both clathrin-mediated endocytosis and lysosomal homeostasis. Recessive loss-of-function mutations in DNAJC6 cause early-onset Parkinsonism, known as PARK19, typically manifesting before age 30[@edvardson2012][@roosen2014].
<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>
<div class="infobox-row"><strong>Gene Symbol</strong></div>
<div class="infobox-row">DNAJC6</div>
<div class="infobox-row"><strong>Full Name</strong></div>
<div class="infobox-row">DnaJ Heat Shock Protein Family (Hsp40) Member C6</div>
<div class="infobox-row"><strong>Chromosomal Location</strong></div>
<div class="infobox-row">19q13.43</div>
<div class="infobox-row"><strong>NCBI Gene ID</strong></div>
<div class="infobox-row">[NCBI Gene: 9829](https://www.ncbi.nlm.nih.gov/gene/9829)</div>
<div class="infobox-row"><strong>OMIM</strong></div>
<div class="infobox-row">[OMIM: 613335](https://www.omim.org/entry/613335)</div>
<div class="infobox-row"><strong>Ensembl ID</strong></div>
<div class="infobox-row">ENSG00000138193</div>
<div class="infobox-row"><strong>UniProt ID</strong></div>
<div class="infobox-row">[Q9Y4X5](https://www.uniprot.org/uniprot/Q9Y4X5)</div>
<div class="infobox-row"><strong>Associated Diseases</strong></div>
<div class="infobox-row">[Parkinson's Disease](/diseases/parkinsons-disease), [PARK19](/diseases/park19), [Early-Onset Parkinsonism](/diseases/early-onset-parkinsonism), [Juvenile Parkinsonism](/diseases/juvenile-parkinsonism)</div>
<div class="infobox-row"><strong>Protein Aliases</strong></div>
<div class="infobox-row">Auxilin-2, DNAJC6</div>
</div>
Function
Synaptic Vesicle Endocytosis
DNAJC6 encodes the auxilin-2 protein, a neuronal co-chaperone of the Hsp40 family that plays a critical role in synaptic vesicle endocytosis. Unlike its close relative DNAJC5 (cystinosin), DNAJC6/Auxilin-2 is specifically expressed in neuronal tissues and regulates clathrin-mediated endocytosis[@roosen2014].
Key Functions in Synaptic Vesicle Cycling:
- Clathrin Uncoating: Auxilin-2 facilitates clathrin coat disassembly during synaptic vesicle recycling, acting as a co-chaperone with Hsc70 to disassemble clathrin triskelia
- Synaptic Transmission: Critical for maintaining synaptic vesicle pools and neurotransmitter release
- Neuronal Homeostasis: Regulates endocytic trafficking in presynaptic terminals
Lysosomal Function and Autophagy
Beyond its role in synaptic vesicle recycling, DNAJC6 is increasingly recognized as a critical regulator of lysosomal function. Recent research (PMID: 41820376(https://pubmed.ncbi.nlm.nih.gov/41820376/)) demonstrates that DNAJC6 truncation mutants cause lysosomal deficiency-induced upregulation of pathologic alpha-synuclein[@dnajc].
Mechanisms:
DNAJC6 localizes to lysosomes and participates in autophagic flux
Loss-of-function mutations impair lysosomal degradation capacity
Lysosomal dysfunction leads to accumulation of toxic protein aggregates
The connection to [alpha-synuclein](/proteins/alpha-synuclein) pathology is a key disease mechanismDisease Associations
PARK19 (Autosomal Recessive Parkinson's Disease)
DNAJC6 mutations cause PARK19, an autosomal recessive form of early-onset Parkinson's disease. Key characteristics include:
- Inheritance: Autosomal recessive (biallelic loss-of-function mutations)
- Early onset: Typically before age 30, often in adolescence or early adulthood
- Rapid progression: Early development of motor complications
- Good levodopa response: Patients respond well to dopaminergic therapy
- Additional features: Some patients develop cognitive impairment and psychiatric symptoms
Juvenile Parkinsonism
DNAJC6 mutations are among the genetic causes of juvenile-onset Parkinsonism (<20 years), along with [PARK2 (parkin/PRKN](/genes/prkn)) and [PINK1](/genes/pink1) mutations.
Pathogenic Mechanisms
DNAJC6 loss-of-function leads to neurodegeneration through multiple interconnected mechanisms:
1. Synaptic Vesicle Recycling Defects
- Impaired synaptic vesicle recycling
- Accumulation of clathrin-coated vesicles
- Depletion of synaptic vesicle pools
- Progressive dopaminergic neuron dysfunction
2. Lysosomal Dysfunction
- Reduced lysosomal enzyme activity
- Impaired autophagic flux
- Accumulation of undigested cellular debris
- Lysosomal deficiency exacerbates protein aggregate formation
3. Alpha-Synuclein Pathology
The connection to [alpha-synuclein](/proteins/alpha-synuclein) is critical:
- Lysosomal deficiency leads to impaired clearance of alpha-synuclein
- Pathologic alpha-synuclein accumulates in neurons
- Forms Lewy bodies characteristic of Parkinson's disease
- Spreads throughout the nervous system in a prion-like manner
Therapeutic Implications
Understanding DNAJC6 function opens several therapeutic avenues:
- Gene therapy: Viral delivery of wild-type DNAJC6 to restore function
- Lysosomal enhancement: Small molecules to boost lysosomal activity
- Alpha-synuclein targeting: Immunotherapies to reduce toxic aggregates
- Neuroprotective strategies: Supporting synaptic and lysosomal homeostasis
Expression
DNAJC6 shows neuron-specific expression:
- Brain: Highest expression in cerebral cortex, [hippocampus](/brain-regions/hippocampus), basal ganglia, and substantia nigra
- Peripheral nervous system: Present in dorsal root ganglia
- Cellular localization: Cytosolic, associated with clathrin-coated vesicles and lysosomes
Allen Brain Atlas Data
Gene Expression
DNAJC6 expression patterns from Allen Brain Atlas:
- Cerebral cortex - High expression in pyramidal neurons (layer 2/3 and layer 5)
- Hippocampus - High expression in CA1 pyramidal neurons and dentate gyrus
- Basal ganglia - High expression in striatum and substantia nigra
- Cerebellum - Moderate expression in Purkinje cells
Single-Cell Expression
DNAJC6 is expressed in:
- Pyramidal neurons (SLC17A7+)
- GABAergic interneurons
- Dopaminergic neurons
- [Astrocytes](/cell-types/astrocytes)
Brain Region Expression Levels
| Region | Expression Level | Data Source |
|--------|-----------------|-------------|
| Cortex | High | Mouse Brain |
| Hippocampus | High | Mouse Brain |
| Striatum | High | Mouse Brain |
| Substantia nigra | Medium | Human MTG |
| Cerebellum | Medium | Mouse Brain |
See Also
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [PARK19](/diseases/park19)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Synaptic Vesicle Cycling](/mechanisms/synaptic-vesicle-cycling-pathway)
- [Lysosomal Dysfunction Pathway](/mechanisms/lysosomal-dysfunction)
- [PINK1](/genes/pink1)
- [PRKN (Parkin)](/genes/prkn)
- [LRRK2](/genes/lrrk2)
- [GBA](/genes/gba)
Brain Atlas Resources
- [Allen Human Brain Atlas - DNAJC6 Expression](https://human.brain-map.org/microarray/search/show?search_term=DNAJC6): Gene expression data across brain regions
- [Allen Cell Type Atlas](https://celltypes.brain-map.org/): Cellular expression patterns in neurons and glia
- [BrainSpan - DNAJC6 Developmental Expression](https://brainspan.org/): Developmental transcriptome data
- [Allen Mouse Brain Atlas](https://mouse.brain-map.org/): Mouse brain expression data
References
[Edvardson S, et al, A deleterious mutation in DNAJC6 causes early-onset progressive Parkinson's disease (2012)](https://doi.org/10.1002/mds.24041)
[Roosen DA, et al, DNAJC6 mutations: Yet another cause of early-onset Parkinson's disease (2014)](https://doi.org/10.1093/brain/awu010)
[Unknown, — Dnajc6 truncation mutant causes lysosomal deficiency-induced upregulation of pathologic alpha-synuclein and neurodegeneration (n.d.)](https://pubmed.ncbi.nlm.nih.gov/41820376/)Pathway Diagram
The following diagram shows the key molecular relationships involving DNAJC6 — DnaJ Heat Shock Protein Family Member A6 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)