Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 1, Pages 141-154Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq452
Keywords
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Funding
- CIHR [84345]
- Parkinson Society of Canada
- National Ataxia Foundation
- Deutsche Forshungsgemeinschaft [DJ 65/4-1]
- FRSQ Chercheur-Boursier senior
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007337] Funding Source: NIH RePORTER
- Medical Research Council [G0800509, G0801418B] Funding Source: researchfish
- MRC [G0800509] Funding Source: UKRI
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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 wildtype 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.
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