Ubiquitylation of synphilin-1 and α-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease
Ubiquitylation of synphilin-1 and α-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease
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DOI：
10.1073/pnas.0401081101
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发表时间：
2004-04-13
影响因子：
11.1
通讯作者：
Engelender, S
中科院分区：
文献类型：
--
作者：
Liani, E;Eyal, A;Engelender, S
帕金森病是一种以路易体形成和多巴胺能神经元死亡为特征的神经退行性疾病。α-突触核蛋白和parkin基因突变导致家族性帕金森病。SynPhilin-1被证明与α-突触核蛋白相互作用，并促进胞质内含物的形成。我们现在报道SynPhilin-1与E3泛素连接酶Siah-1和Siah-2相互作用。Siah蛋白在体外和体内泛素化SynPhilin-1，通过泛素-蛋白酶体系统促进其降解。蛋白酶体不能降解SynPhilin-1/Siah复合体导致泛素化胞液内含物的强健形成。泛素化是形成包涵体所必需的，因为Siah-1的一个催化不活跃的突变体仍然与SynPhilin-1结合，不能促进包涵体的形成。与突触素-1一样，α-突触核蛋白在完整细胞中与Siah结合，但与Siah-2的相互作用比与Siah-1强得多。体外实验表明，Siah-2单联核苷酸化α-突触核蛋白。进一步的证据表明，Siah蛋白可能在包涵体的形成中发挥作用，这来自PD患者路易体中Siah免疫反应性的证明。
Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.