Ataxin-3 (ATXN3) <div class="infobox" style="float:right; background:#f8f9fa; border:1px solid #ddd; padding:10px; margin:0 0 10px 10px; width:280px;">
Overview
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Ataxin-3 (ATXN3) <div class="infobox" style="float:right; background:#f8f9fa; border:1px solid #ddd; padding:10px; margin:0 0 10px 10px; width:280px;">
Overview
Mermaid diagram (expand to render)
Ataxin-3 (ATXN3) , also known as Machado-Joseph disease protein , is a cysteine protease deubiquitinase (DUB) that cleaves polyubiquitin chains and regulates protein degradation. CAG repeat expansion in ATXN3 causes Spinocerebellar Ataxia Type 3 (SCA3) , also known as Machado-Joseph disease (MJD) , the most common dominant spinocerebellar ataxia worldwide.[@kawaguchi1994]
Structure and Domains Ataxin-3 contains:
Josephin domain — catalytic domain with deubiquitinase activity (N-terminal)Polyglutamine tract — CAG repeat region (normal <44; pathogenic >52)Ubiquitin-interacting motifs (UIMs) — typically 2-3 UIMs that bind ubiquitin chainsNuclear localization signal — regulates subcellular distributionThe Josephin domain adopts a papain-like fold and contains the catalytic cysteine (C14) and histidine (H158) residues required for deubiquitinase activity.[@mao2005]
Normal Function
Deubiquitinase Activity Ataxin-3 functions as a ubiquitin-specific protease:
Polyubiquitin chain cleavage — Preferentially cleaves K63-linked chainsChain editing — Converts K63 to K48 linkages for proteasomal targetingUbiquitin homeostasis — Maintains cellular ubiquitin pools
DNA Repair Ataxin-3 participates in DNA damage response:[@burnett2006]
Transcription-coupled repair — Interacts with RAD23 proteinsHistone modification — Deubiquitinates histones at damage sitesGenome stability — Protects against DNA damage accumulationProtein Quality Control
ER-associated degradation (ERAD) — Facilitates clearance of misfolded proteinsAggresome formation — Regulates trafficking of aggregated proteinsChaperone interactions — Associates with HSP70 and HSP40Role in Neurodegeneration
SCA3/Machado-Joseph Disease CAG expansion causes SCA3 through:[@schmidt2019]
Protein Aggregation
Nuclear inclusions — Mutant ataxin-3 forms intranuclear aggregatesUbiquitin-positive inclusions — Contain ubiquitin, proteasome componentsSequestration — Wild-type ataxin-3 and other proteins trapped in inclusions
Loss of Deubiquitinase Function
Impaired ubiquitin recycling — Reduced proteasome efficiencyDefective DNA repair — Accumulation of DNA damage in [neurons](/entities/neurons)ERAD dysfunction — Misfolded protein accumulation
Clinical Features SCA3 is characterized by:
Progressive ataxia — Gait and limb incoordinationOphthalmoplegia — Eye movement abnormalitiesPeripheral neuropathy — Sensory and motor deficitsParkinsonism — Extrapyramidal features in some patientsPyramidal signs — Spasticity and hyperreflexiaSelective Vulnerability Neuronal populations affected include:
Pontine nuclei
Substantia nigra
Dentate nucleus
Inferior olive
Spinal motor neurons
Therapeutic Targeting
Antisense Oligonucleotides
ATXN3 ASOs — Reduce mutant protein expressionAllele-selective approaches — Target expanded allele specificallyDeubiquitinase Modulation | Strategy | Mechanism | Status |
Gene Therapy
AAV-miRNA — Knockdown of ATXN3 expressionCRISPR editing — Targeting CAG repeat expansionProtein Interactions | Partner | Function | Disease Relevance |
See Also
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
External Links
[UniProt: P54252](https://www.uniprot.org/uniprot/P54252)
[PDB structures](https://www.rcsb.org/search?q=uniprot:P54252)
References
[Kawaguchi Y, et al, CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 (1994)](https://doi.org/10.1038/ng0894-221)
[Mao Y, et al, Crystal structure of the Josephin domain of ataxin-3 (2005)](https://doi.org/10.1038/sj.emboj.7600300)
[Burnett B, et al, DNA damage is a pathogenic trigger for ataxin-3 in Drosophila models of SCA3 (2006)](https://doi.org/10.1093/hmg/ddl430)
[Schmidt T, et al, Protein surveillance and quality control in SCA3 (2019)](https://doi.org/10.1007/s00401-019-02061-2)
Pathway Diagram The following diagram shows the key molecular relationships involving Ataxin-3 (ATXN3) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
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