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. © The Author 2010. Published by Oxford University Press. All rights reserved.
CITATION STYLE
Durcan, T. M., Kontogiannea, M., Thorarinsdottir, T., Fallon, L., Williams, A. J., Djarmati, A., … Fon, E. A. (2011). The machado-joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability. Human Molecular Genetics, 20(1), 141–154. https://doi.org/10.1093/hmg/ddq452
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