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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 selfubiquitination. 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.
Originalsprache | Englisch |
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Zeitschrift | Human Molecular Genetics |
Jahrgang | 20 |
Ausgabenummer | 1 |
Seiten (von - bis) | 141-154 |
Seitenumfang | 14 |
ISSN | 0964-6906 |
DOIs | |
Publikationsstatus | Veröffentlicht - 01.01.2011 |
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Parkin-mediated ubiquitination and Parkinson's disease: Role of ubiquitin-conjugating enzymes (E2s) and ubiquitin-interacting motif (UIM)-containing proteins
Westenberger, A. (Projektleiter*in (PI)) & Paulson, H. L. (Beteiligte*r Wissenschaftler*in)
01.01.10 → 31.12.11
Projekt: DFG-Projekte › DFG-Stipendien: Research Fellowships