%K Parkinson’s disease, α-synuclein, SUMOylatio, nubiquitination, aggregation
%A R Rott
%A R Szargel
%A V Shani
%A H Hamza
%A M Savyon
%A F Abd Elghani
%A R Bandopadhyay
%A S Engelender
%V 114
%X α-Synuclein accumulation is a pathological hallmark of Parkinson’s disease (PD). Ubiquitinated α-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 α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in α-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases α-synuclein levels by relieving the inhibition exerted on α-synuclein proteasomal degradation. α-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 α-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of α-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 α-synuclein by PIAS2 promotes α-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on α-synuclein. Second, SUMOylation facilitates α-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of α-synuclein SUMOylation provide a strategy to reduce α-synuclein levels and possibly aggregation in PD.
%J Proceedings of the National Academy of Sciences of the United States of America
%N 50
%I National Academy of Sciences
%L discovery10032511
%D 2017
%O This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
%T SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation
%P 13176-13181