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The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability.

Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson's disease, as a novel ataxin-3 binding partner. The interaction between ataxin-3 and parkin is direct, involves multiple domains and is greatly enhanced by parkin self-ubiquitination. Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells. Compared with wild-type ataxin-3, MJD-linked polyQ-expanded mutant ataxin-3 is more active, possibly owing to its greater efficiency at DUB K27- and K29-linked Ub conjugates on parkin. Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway. The finding is consistent with the reduction in parkin levels observed in the brains of transgenic mice over-expressing polyQ-expanded but not wild-type ataxin-3, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of its parkinsonian features.

Pubmed ID: 20940148


  • Durcan TM
  • Kontogiannea M
  • Thorarinsdottir T
  • Fallon L
  • Williams AJ
  • Djarmati A
  • Fantaneanu T
  • Paulson HL
  • Fon EA


Human molecular genetics

Publication Data

January 1, 2011

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id: 84345
  • Agency: Medical Research Council, Id: G0800509
  • Agency: NIGMS NIH HHS, Id: T32 GM007337

Mesh Terms

  • Animals
  • Ataxin-3
  • Autophagy
  • HEK293 Cells
  • Humans
  • Machado-Joseph Disease
  • Mice
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Protein Stability
  • Repressor Proteins
  • Transfection
  • Ubiquitin-Protein Ligases
  • Ubiquitination