The Machado–Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
- 11 October 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 20 (1), 141-154
- https://doi.org/10.1093/hmg/ddq452
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 self-ubiquitination. 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.This publication has 89 references indexed in Scilit:
- Neurogranin enhances synaptic strength through its interaction with calmodulinThe EMBO Journal, 2009
- The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophreniaMolecular Psychiatry, 2009
- Common variants on chromosome 6p22.1 are associated with schizophreniaNature, 2009
- Common variants conferring risk of schizophreniaNature, 2009
- Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based studyThe Lancet, 2009
- Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic riskMolecular Psychiatry, 2008
- Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorderNature Genetics, 2008
- Estimation of significance thresholds for genomewide association scansGenetic Epidemiology, 2008
- Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controlsNature, 2007
- A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signallingNature, 2006