Journal article
The Machado―Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
Human molecular genetics, Vol.20(1), pp.141-154
2011
DOI: 10.1093/hmg/ddq452
PMID: 20940148
Abstract
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.
Details
- Title: Subtitle
- The Machado―Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
- Creators
- Thomas M DURCAN - Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, CanadaMaria KONTOGIANNEA - Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, CanadaThorhildur THORARINSDOTTIR - Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, CanadaLara FALLON - Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, CanadaAislinn J WILLIAMS - Department of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, United StatesAna DJARMATI - Department of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, United StatesTadeu FANTANEANU - Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, CanadaHenry L PAULSON - Department of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, United StatesEdward A FON - Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.20(1), pp.141-154
- Publisher
- Oxford University Press; Oxford
- DOI
- 10.1093/hmg/ddq452
- PMID
- 20940148
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 2011
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984065837502771
Metrics
14 Record Views