SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation

alpha-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated alpha-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates alpha-synuclein degradation. We report that PIAS2 promotes SUMOylation of alpha-synuclein, leading to a decrease in alpha-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in alpha-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases alpha-synuclein levels by relieving the inhibition exerted on alpha-synuclein proteasomal degradation. alpha-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated alpha-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of alpha-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of alpha-synuclein by PIAS2 promotes alpha-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on alpha-synuclein. Second, SUMOylation facilitates alpha-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of alpha-synuclein SUMOylation provide a strategy to reduce alpha-synuclein levels and possibly aggregation in PD.