The Machado–Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
In: Human Molecular Genetics, Jg. 20 (2010-10-11), S. 141-154
Online
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Zugriff:
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.
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The Machado–Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
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Autor/in / Beteiligte Person: | Durcan, Thomas M. ; Paulson, Henry L. ; Kontogiannea, Maria ; Fallon, Lara ; Fon, Edward A. ; Fantaneanu, Tadeu ; Williams, Aislinn J. ; Djarmati, Ana ; Thorarinsdottir, Thorhildur |
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Zeitschrift: | Human Molecular Genetics, Jg. 20 (2010-10-11), S. 141-154 |
Veröffentlichung: | Oxford University Press (OUP), 2010 |
Medientyp: | unknown |
ISSN: | 1460-2083 (print) ; 0964-6906 (print) |
DOI: | 10.1093/hmg/ddq452 |
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