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

Authors: Lee, James T.; Wheeler, Tiffany C.; Li, Lian; Chin, Lih-Shen

Source: Human Molecular Genetics, Volume 17, Number 6, 15 March 2008 , pp. 906-917(12)

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Abstract:

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.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddm363

Publication date: 2008-03-15

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