- UniProt: [P54252](https://www.uniprot.org/uniprot/P54252)
- Gene: [ATXN3](/entities/atxn3)
- Aliases: AT3, SCA3, MJD, MJD1a
- MW: ~42 kDa (varies with polyQ length)
- Localization: Nucleus, cytoplasm
- PDB: [2L86](https://www.rcsb.org/structure/2L86)
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.
¶ 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 chains
- Nuclear localization signal — regulates subcellular distribution
The Josephin domain adopts a papain-like fold and contains the catalytic cysteine (C14) and histidine (H158) residues required for deubiquitinase activity.
Ataxin-3 functions as a ubiquitin-specific protease:
- Polyubiquitin chain cleavage — Preferentially cleaves K63-linked chains
- Chain editing — Converts K63 to K48 linkages for proteasomal targeting
- Ubiquitin homeostasis — Maintains cellular ubiquitin pools
Ataxin-3 participates in DNA damage response:
- Transcription-coupled repair — Interacts with RAD23 proteins
- Histone modification — Deubiquitinates histones at damage sites
- Genome stability — Protects against DNA damage accumulation
- ER-associated degradation (ERAD) — Facilitates clearance of misfolded proteins
- Aggresome formation — Regulates trafficking of aggregated proteins
- Chaperone interactions — Associates with HSP70 and HSP40
CAG expansion causes SCA3 through:
- Nuclear inclusions — Mutant ataxin-3 forms intranuclear aggregates
- Ubiquitin-positive inclusions — Contain ubiquitin, proteasome components
- Sequestration — Wild-type ataxin-3 and other proteins trapped in inclusions
- Impaired ubiquitin recycling — Reduced proteasome efficiency
- Defective DNA repair — Accumulation of DNA damage in neurons
- ERAD dysfunction — Misfolded protein accumulation
SCA3 is characterized by:
- Progressive ataxia — Gait and limb incoordination
- Ophthalmoplegia — Eye movement abnormalities
- Peripheral neuropathy — Sensory and motor deficits
- Parkinsonism — Extrapyramidal features in some patients
- Pyramidal signs — Spasticity and hyperreflexia
Neuronal populations affected include:
- Pontine nuclei
- Substantia nigra
- Dentate nucleus
- Inferior olive
- Spinal motor neurons
- ATXN3 ASOs — Reduce mutant protein expression
- Allele-selective approaches — Target expanded allele specifically
| Strategy |
Mechanism |
Status |
| DUB activators |
Enhance residual activity |
Preclinical |
| Ubiquitin mimetics |
Boost degradation |
Discovery |
| Proteostasis enhancers |
Improve clearance |
Preclinical |
- AAV-miRNA — Knockdown of ATXN3 expression
- CRISPR editing — Targeting CAG repeat expansion
| Partner |
Function |
Disease Relevance |
| RAD23A/B |
DNA repair |
Nucleotide excision repair |
| VCP/p97 |
ERAD |
Protein degradation |
| HHR23A |
DNA repair |
Genome stability |
| Ubiquitin |
Substrate |
Deubiquitinase activity |