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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Ubiquitination of 
-synuclein by Siah-1 promotes -synuclein aggregation and apoptotic cell death
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 
-synuclein cause autosomal dominant familial Parkinson's disease (PD). Moreover, -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 -synuclein species in Lewy bodies, the regulation of -synuclein ubiquitination and its role in Lewy body formation and neurodegeneration remain poorly understood. Here, we report that -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 -synuclein in vivo. The ubiquitination of -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 -synuclein for degradation by the proteasome, but rather, it promotes -synuclein aggregation and enhances -synuclein toxicity. Our findings suggest that Siah-1-mediated -synuclein ubiquitination may play a critical role in Lewy body formation and PD pathogenesis.
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