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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >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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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

机译：SIAH对synphilin-1和α-突触核蛋白的泛化作用及其在细胞包裹体和路易体中的存在暗示着帕金森氏病的作用

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Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in α-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with α-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SlAH-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, α-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 α-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.
机译：帕金森氏病（PD）是一种神经退行性疾病，其特征是路易体形成和多巴胺能神经元死亡。 α-突触核蛋白和Parkin的突变会导致家族性PD。 Synphilin-1已显示与α-突触核蛋白相互作用，并促进胞质内含物的形成。现在，我们报告synphilin-1与E3泛素连接酶SIAH-1和SlAH-2相互作用。 SIAH蛋白在体内和体外都泛素化了synphilin-1，促进了泛素-蛋白酶体系统的降解。蛋白酶体不能降解synphilin-1 SIAH复合物会导致泛素化胞质内含物的形成。包涵体形成需要泛素化，因为SIAH-1的催化失活突变体仍与synphilin-1结合，不能促进包涵体。像synphilin-1一样，α-突触核蛋白与完整细胞中的SIAH缔合，但与SIAH-2的相互作用比与SIAH-1的相互作用强得多。体外实验表明，SIAH-2单泛素化了α-突触核蛋白。 SIAH蛋白可能在包涵体形成中起作用的进一步证据来自PD患者路易体中SIAH免疫反应性的证明。

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