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

Abstract

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