Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death.
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.
Lee
James T
JT
Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322-3090, USA.
Wheeler
Tiffany C
TC
Li
Lian
L
Chin
Lih-Shen
LS
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D006367:HeLa Cells; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D012995:Solubility; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins