Journal Article

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

Thomas M. Durcan, Maria Kontogiannea, Thorhildur Thorarinsdottir, Lara Fallon, Aislinn J. Williams, Ana Djarmati, Tadeu Fantaneanu, Henry L. Paulson and Edward A. Fon

in Human Molecular Genetics

Volume 20, issue 1, pages 141-154
Published in print January 2011 | ISSN: 0964-6906
Published online October 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq452
The Machado–Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability

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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 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.

Journal Article.  7225 words.  Illustrated.

Subjects: Genetics and Genomics

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