Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London WC1N 1PJ, United Kingdom.
Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13176-13181. doi: 10.1073/pnas.1704351114. Epub 2017 Nov 27.
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.
α-突触核蛋白的积累是帕金森病（PD）的病理标志。泛素化的α-突触核蛋白被靶向到蛋白酶体或溶酶体降解。在这里，我们确定 SUMO 化是一种主要的机制，可以对抗不同的 E3 泛素连接酶的泛素化，并调节α-突触核蛋白的降解。我们报告说，PIAS2 促进α-突触核蛋白的 SUMO 化，导致 SIAH 和 Nedd4 泛素连接酶对α-突触核蛋白的泛素化减少，并导致其积累和聚集形成包涵体。这与α-突触核蛋白从细胞中的释放增加有关。SUMO E1 抑制剂，白果内酯，通过减轻对α-突触核蛋白蛋白酶体降解的抑制作用，降低α-突触核蛋白的水平。与野生型蛋白相比，α-突触核蛋白病突变体的 SUMO 化程度更高，这与聚集和包涵体形成增加有关。我们在 PD 大脑中检测到 PIAS2 表达和 SUMO 化的α-突触核蛋白的明显增加，为疾病中α-突触核蛋白 SUMO 化的上调提供了一个因果机制。我们还发现，在黑质神经元中的 Lewy 体中含有 SUMO1 和 PIAS2。我们的观察结果表明，PIAS2 对α-突触核蛋白的 SUMO 化通过两种相互增强的机制促进α-突触核蛋白的聚集。首先，它对α-突触核蛋白有直接的促聚集作用。其次，SUMO 化通过阻止其依赖于泛素的降解途径并促进其积累，从而促进α-突触核蛋白的聚集。因此，α-突触核蛋白 SUMO 化的抑制剂提供了一种减少 PD 中α-突触核蛋白水平和可能聚集的策略。
