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Human Molecular Genetics Advance Access originally published online on December 7, 2007
Human Molecular Genetics 2008 17(6):906-917; doi:10.1093/hmg/ddm363
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ubiquitination of {alpha}-synuclein by Siah-1 promotes {alpha}-synuclein aggregation and apoptotic cell death

James T. Lee1, Tiffany C. Wheeler2, Lian Li1,2 and Lih-Shen Chin1,2,*

1 Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322-3090, USA 2 Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA

* To whom correspondence should be addressed. Tel: +1 4047270361; Fax: +1 4047270365; Email: chinl{at}pharm.emory.edu

Received August 23, 2007; Revised October 31, 2007; Accepted December 5, 2007

Point mutations and gene multiplication of {alpha}-synuclein cause autosomal dominant familial Parkinson's disease (PD). Moreover, {alpha}-synuclein- and ubiquitin-positive inclusion bodies are the pathological hallmarks of PD and several other neurodegenerative diseases, such as dementia with Lewy bodies and multiple system atrophy. Despite the presence of ubiquitinated {alpha}-synuclein species in Lewy bodies, the regulation of {alpha}-synuclein ubiquitination and its role in Lewy body formation and neurodegeneration remain poorly understood. Here, we report that {alpha}-synuclein interacts and colocalizes with mammalian seven in absentia homologue-1 (Siah-1), a RING-type E3 ubiquitin-protein ligase. Siah-1 binds the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 and facilitates mono- and di-ubiquitination of {alpha}-synuclein in vivo. The ubiquitination of {alpha}-synuclein by Siah-1 is disrupted by the PD-linked A30P mutation but not by A53T mutation. We find that Siah-1-mediated ubiquitination does not target {alpha}-synuclein for degradation by the proteasome, but rather, it promotes {alpha}-synuclein aggregation and enhances {alpha}-synuclein toxicity. Our findings suggest that Siah-1-mediated {alpha}-synuclein ubiquitination may play a critical role in Lewy body formation and PD pathogenesis.


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