DNAJC5 Gene

📖 Wiki Page

gene1746 wordssynced 2026-04-02

DNAJC5 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DNAJC5 — DnaJ Heat Shock Protein Family (Hsp40) Member C5</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>DNAJC5</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>DnaJ Heat Shock Protein Family (Hsp40) Member C5</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>10q24.32</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/80315" target="_blank">80315</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000170584" target="_blank">ENSG00000170584</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/611021" target="_blank">611021</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9H3X5" target="_blank">Q9H3X5</a></td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Cysteine String Protein (CSP)</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>198 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>22.4 kDa</td>
</tr>
<tr>
<td class="label">Brain Expression</td>
<td>High: cortex, hippocampus, basal ganglia</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Synaptic vesicles, endoplasmic reticulum</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Parkinson's

...

DNAJC5 Gene

DNAJC5 — DnaJ Heat Shock Protein Family (Hsp40) Member C5

Introduction

Dnajc5 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Mermaid diagram (expand to render)

DNAJC5 (DnaJ Heat Shock Protein Family (Hsp40) Member C5), also known as Cysteine String Protein (CSP), is a gene located on chromosome 10q24.32 that encodes a critical molecular chaperone protein expressed predominantly in neuronal tissues["@ncbi"]. CSP is essential for synaptic vesicle function, protein quality control, and neuronal survival. Mutations in DNAJC5 cause autosomal dominant adult-onset neuronal ceroid lipofuscinosis (ANCL), and the protein has been implicated in the pathogenesis of Parkinson's disease through its role in [alpha-synuclein](/proteins/alpha-synuclein) metabolism and synaptic homeostasis["@cadzow2016"][@benitez2015].

The DNAJC5 gene consists of 6 exons and encodes a 198-amino acid protein with a molecular weight of approximately 22.4 kDa["@ncbi"]. The protein is characterized by a conserved J-domain at its N-terminus, a glycine-rich flexible linker region, and a cysteine-rich "string" domain at the C-terminus that undergoes palmitoylation for membrane association["@chamberlain1997"].

Gene Structure and Evolution

The DNAJC5 gene spans approximately 12.5 kb on chromosome 10q24.32 and contains 6 exons encoding the CSP protein[@ncbi]. CSP is highly conserved throughout evolution, with orthologs present in Drosophila melanogaster (Drosophila CSP), Caenorhabditis elegans (dnjc-5), and yeast (Sec63p). The conservation of CSP across species underscores its fundamental role in cellular function.

Alternative Splicing

DNAJC5 undergoes alternative splicing, producing multiple transcript variants. The major brain isoform lacks the C-terminal variable region but retains the essential functional domains. This alternative splicing is tissue-specific, with neuronal tissues preferentially expressing the isoform lacking the variable region[@evans2001].

Protein Structure and Function

CSP contains several distinct structural domains that mediate its diverse functions:

J-Domain

The N-terminal J-domain (residues 1-70) is the signature feature of Hsp40 family proteins. This domain recruits and stimulates the ATPase activity of Hsp70 chaperones, including [Hsc70](/proteins/hspa8-protein)[@chamberlain1997]. Through this interaction, CSP facilitates the folding of nascent polypeptides, refolding of misfolded proteins, and disassembly of protein complexes.

Glycine-Rich Linker

The central glycine-rich region (residues 71-140) provides flexibility and mediates protein-protein interactions. This region contains multiple phosphorylation sites that regulate CSP function[@nie1999].

Cysteine String Domain

The C-terminal cysteine string domain (residues 141-198) contains 13 cysteine residues, 10 of which are palmitoylated for membrane anchoring to synaptic vesicles[@chamberlain1997]. The palmitoylated cysteine string targets CSP to synaptic vesicles, where it constitutes up to 1% of total synaptic vesicle protein[@greaves2008].

CSP Functions in Neurons

CSP performs multiple essential functions in [neurons](/entities/neurons):

Synaptic Vesicle Chaperone: CSP prevents protein aggregation on synaptic vesicles and assists in the folding of synaptic vesicle proteins[@chamberlain1997].

SNARE Complex Assembly: CSP co-assembles with the SNARE machinery and is essential for synaptic vesicle fusion[@sharma2012].

Calcium Homeostasis: CSP regulates calcium release from the endoplasmic reticulum through interactions with ryanodine receptors[@wang2011].

Mitochondrial Quality Control: CSP translocates to mitochondria under stress conditions, where it protects against oxidative damage[@chen2010].

[Autophagy](/entities/autophagy) Regulation: CSP interacts with autophagy machinery and regulates the clearance of misfolded proteins[@zhang2018].

Expression Pattern

Brain Regional Expression

DNAJC5 is highly expressed throughout the central nervous system, with the highest expression levels in:

Cerebral [Cortex](/brain-regions/cortex): Particularly layer 5 pyramidal neurons
[Hippocampus](/brain-regions/hippocampus): CA1-CA3 regions and dentate gyrus
Basal Ganglia: Striatum and substantia nigra pars compacta
Cerebellum: Purkinje cells and granule cells
Brainstem: Motor nuclei and reticular formation

Expression data from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=DNAJC5) confirms high cortical and subcortical expression[@ncbi].

Cellular Localization

Within neurons, CSP localizes to:

Synaptic vesicles (predominant)
Endoplasmic reticulum
Mitochondria (under stress conditions)
Cytosol

Disease Associations

Adult-Onset Neuronal Ceroid Lipofuscinosis (ANCL)

Dominant mutations in DNAJC5 cause ANCL (also known as Kufs disease type A), a rare neurodegenerative disorder characterized by:[@cadzow2016][@benitez2015]

Age of Onset: 30-50 years
Clinical Features:
Progressive dementia
Motor dysfunction (ataxia, parkinsonism)
Seizures
Visual loss (later stages)
Neuropathology:
Neuronal loss and gliosis
Accumulation of ceroid lipopigments (autofluorescent storage material)
Subcortical and cortical atrophy
Inheritance: Autosomal dominant

Known Pathogenic Mutations

| Mutation | Type | Effect |
|----------|------|--------|
| C105F | Missense | Disrupts J-domain function |
| L116del | In-frame deletion | Impairs chaperone activity |
| D205H | Missense | Reduces protein stability |

Parkinson's Disease

DNAJC5 has been implicated in Parkinson's disease pathogenesis through multiple mechanisms:[@zhang2018][@garcapartida2020]

[Alpha-Synuclein](/proteins/alpha-synuclein) Interaction: CSP regulates alpha-synuclein aggregation and clearance through the autophagy-lysosome pathway.

Synaptic Dysfunction: Loss of CSP function leads to impaired synaptic vesicle cycling and neurotransmitter release.

Oxidative Stress: CSP-deficient neurons show increased vulnerability to oxidative stress.

Mitochondrial Dysfunction: CSP mutations impair mitochondrial quality control.

Other Neurodegenerative Conditions

Huntington's Disease: CSP levels are altered in HD models and may influence mutant [huntingtin](/proteins/huntingtin-protein) aggregation[@zabel2002]
[Alzheimer's Disease](/diseases/alzheimers-disease): CSP is implicated in [amyloid-beta](/proteins/amyloid-beta) and [tau](/proteins/tau) metabolism
Amyotrophic Lateral Sclerosis (ALS): CSP protective functions may be relevant to motor neuron survival

Molecular Mechanisms

CSP in Synaptic Transmission

CSP is essential for normal synaptic transmission through its role in:[@chamberlain1997][@sharma2012]

Vesicle Priming: CSP participates in SNARE complex assembly during vesicle priming

Fusion: CSP is required for efficient synaptic vesicle fusion

Endocytosis: CSP regulates clathrin-mediated endocytosis

CSP in Protein Quality Control

The J-domain of CSP recruits Hsp70 for protein refolding and quality control:[@chamberlain1997][@chen2010]

CSP (J-domain) → Recruits Hsc70 → ATP hydrolysis → Protein refolding/clearance

CSP in Autophagy

CSP regulates selective autophagy through interactions with:[@zhang2018]

p62/SQSTM1
LC3/GABARAP
Hsc70

Therapeutic Implications

Small Molecule Chaperones

Pharmacological chaperones that stabilize CSP structure are being investigated for ANCL treatment. 4-phenylbutyric acid (PBA) and sodium butyrate have shown promise in cellular models[@wuur2019].

Gene Therapy

AAV-mediated gene delivery of wild-type DNAJC5 is being explored for ANCL treatment. Viral vectors expressing CSP under neuronal promoters have shown efficacy in mouse models[@soleman2021].

Small Molecule Activators

Compounds that enhance Hsp70 activity (to boost CSP-Hsp70 complex function) represent another therapeutic approach. Hsp70 activators such as geranylgeranylacetone are in development[@jinwal2010].

Key Publications

[@ncbi]: NCBI Gene: [DNAJC5](https://www.ncbi.nlm.nih.gov/gene/80315)

[@cadzow2016]: Cadzow M, et al. (2016). A dominant-negative mutation in DNAJC5 causes autosomal dominant adult-onset neuronal ceroid lipofuscinosis. Brain, 139(Pt 2), 338-354. [DOI](https://doi.org/10.1093/brain/awv219)

[@benitez2015]: Benitez BA, et al. (2015). Exome sequencing is a powerful diagnostic tool for neuronal ceroid lipofuscinosis. JAMA Neurol, 72(9), 1034-1040.

[@chamberlain1997]: Chamberlain LH, Burgoyne RD (1997). The cysteine-string protein function. Biochem J, 322 (Pt 3), 859-865.

[@evans2001]: Evans GJ, et al. (2001). Alternative splicing of cysteine-string protein RNA. Brain Res Mol Brain Res, 95(1-2), 131-139.

[@nie1999]: Nie Z, et al. (1999). Phosphorylation of cysteine string protein. Biochem J, 340 (Pt 1), 51-57.

[@greaves2008]: Greaves J, et al. (2008). Palmitoylation of cysteine-string protein. Biochem J, 413(3), 479-491.

[@sharma2012]: Sharma M, et al. (2012). CSPalpha knockout mice. J Neurosci, 32(21), 7235-7243.

[@wang2011]: Wang J, et al. (2011). Calcium release from ryanodine receptors. Cell Calcium, 49(1), 32-41.

[@chen2010]: Chen L, et al. (2010). Mitochondrial targeting by CSP. J Cell Sci, 123(Pt 22), 3846-3855.

[@zhang2018]: Zhang X, et al. (2018). DNAJC5 and autophagy in neurodegeneration. Autophagy, 14(11), 1945-1961.

[@garcapartida2020]: García-Partida JA, et al. (2020). DNAJC5 in alpha-synuclein pathology. Mov Disord, 35(10), 1783-1794.

[@zabel2002]: Zabel C, et al. (2002). Changes in brain protein expression in Huntington's disease. Mol Cell Proteomics, 1(10), 787-797.

[@wuur2019]:wuur P, et al. (2019). Pharmacological chaperones for ANCL. J Clin Invest, 129(5), 1878-1893.

[@soleman2021]: Soleman F, et al. (2021). AAV gene therapy for DNAJC5 mutation. Mol Ther, 29(6), 2212-2225.

[@jinwal2010]: Jinwal UK, et al. (2010). Hsp70 activation for neurodegeneration. Nat Rev Neurosci, 11(7), 395-406.

Allen Brain Atlas Data

Gene Expression: Human brain expression data from Allen Brain Atlas shows DNAJC5 is expressed across multiple brain regions with highest expression in cerebral cortex and hippocampus. Expression patterns are consistent with its role in synaptic vesicle trafficking.

Single-Cell Expression: Single-cell RNA-seq data from the Allen Brain Cell Atlas shows DNAJC5 expression across major brain cell types, with enrichment in neurons and astrocytes.

External Resources:

[Allen Brain Atlas Gene Expression](https://human.brain-map.org/gene/show?gene_id=ENSG00000040538)
[Allen Brain Cell Atlas - DNAJC5](https://celltype.brain-science.org/)
[Allen Brain Atlas - Transcriptomics](https://portal.brain-map.org/explore/transcriptomics)

Data Source: Allen Human Brain Atlas, Human Middle Temporal Gyrus (MTG) dataset.

External Links

[NCBI Gene*: [https://www.ncbi.nlm.nih.gov/gene/80315](https://www.ncbi.nlm.nih.gov/gene/80315)](/institutions/nih)
[Ensembl*: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000170584](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000170584)](/genes/ar)
[OMIM*: [https://omim.org/entry/611021](https://omim.org/entry/611021)](/entities/htt)
[UniProt*: [https://www.uniprot.org/uniprot/Q9H3X5](https://www.uniprot.org/uniprot/Q9H3X5)](/entities/htt)
Allen Human Brain Atlas: [DNAJC5 expression](https://human.brain-map.org/microarray/search/show?search_term=DNAJC5)
PubMed: [Search DNAJC5 publications](https://pubmed.ncbi.nlm.nih.gov/?term=DNAJC5+cysteine+string+protein)

Background

The study of Dnajc5 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

Unknown, NCBI Gene: DNAJC5 (n.d.)

Cadzow M, et al, A dominant-negative mutation in DNAJC5 causes autosomal dominant adult-onset neuronal ceroid lipofuscinosis (2016)

Benitez BA, et al, Exome sequencing is a powerful diagnostic tool for neuronal ceroid lipofuscinosis (2015)

Chamberlain LH, Burgoyne RD, The cysteine-string protein function (1997)

Evans GJ, et al, Alternative splicing of cysteine-string protein RNA (2001)

Nie Z, et al, Phosphorylation of cysteine string protein (1999)

Greaves J, et al, Palmitoylation of cysteine-string protein (2008)

Sharma M, et al, CSPalpha knockout mice (2012)

Wang J, et al, Calcium release from ryanodine receptors (2011)

Chen L, et al, Mitochondrial targeting by CSP (2010)

Zhang X, et al, DNAJC5 and autophagy in neurodegeneration (2018)

García-Partida JA, et al, DNAJC5 in alpha-synuclein pathology (2020)

Zabel C, et al, Changes in brain protein expression in Huntington's disease (2002)

Wuur P, et al, Pharmacological chaperones for ANCL (2019)

Soleman F, et al, AAV gene therapy for DNAJC5 mutation (2021)

Jinwal UK, et al, Hsp70 activation for neurodegeneration (2010)

Pathway Diagram

The following diagram shows the key molecular relationships involving DNAJC5 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

DNAJC5 Gene

DNAJC5 Gene

DNAJC5 Gene

DNAJC5 — DnaJ Heat Shock Protein Family (Hsp40) Member C5

Introduction

Overview

Gene Structure and Evolution

Alternative Splicing

Protein Structure and Function

J-Domain

Glycine-Rich Linker

Cysteine String Domain

CSP Functions in Neurons

Expression Pattern

Brain Regional Expression

Cellular Localization

Disease Associations

Adult-Onset Neuronal Ceroid Lipofuscinosis (ANCL)

Known Pathogenic Mutations

Parkinson's Disease

Other Neurodegenerative Conditions

Molecular Mechanisms

CSP in Synaptic Transmission

CSP in Protein Quality Control

CSP in Autophagy

Therapeutic Implications

Small Molecule Chaperones

Gene Therapy

Small Molecule Activators

Key Publications

Allen Brain Atlas Data

See Also

External Links

Background

References

Pathway Diagram