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, Edward A. Fon*

*Korrespondierende/r Autor/-in für diese Arbeit
70 Zitate (Scopus)

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.

OriginalspracheEnglisch
ZeitschriftHuman Molecular Genetics
Jahrgang20
Ausgabenummer1
Seiten (von - bis)141-154
Seitenumfang14
ISSN0964-6906
DOIs
PublikationsstatusVeröffentlicht - 01.01.2011

Fingerprint

Untersuchen Sie die Forschungsthemen von „The machado-joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability“. Zusammen bilden sie einen einzigartigen Fingerprint.

Zitieren