Liani Esti, Eyal Allon, Avraham Eyal, Shemer Revital, Szargel Raymonde, Berg Daniela, Bornemann Antje, Riess Olaf, Ross Christopher A, Rott Ruth, Engelender Simone
Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5500-5. doi: 10.1073/pnas.0401081101. Epub 2004 Apr 2.
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.
帕金森病（PD）是一种神经退行性疾病，其特征为路易小体形成和多巴胺能神经元死亡。α-突触核蛋白和帕金蛋白的突变会导致家族性帕金森病。研究表明，突触结合蛋白-1与α-突触核蛋白相互作用，并促进胞质内含物的形成。我们现在报告，突触结合蛋白-1与E3泛素连接酶SIAH-1和SIAH-2相互作用。SIAH蛋白在体外和体内都会使突触结合蛋白-1泛素化，促进其通过泛素-蛋白酶体系统降解。蛋白酶体无法降解突触结合蛋白-1/SIAH复合物会导致泛素化胞质内含物大量形成。泛素化是内含物形成所必需的，因为仍与突触结合蛋白-1结合的SIAH-1催化失活突变体无法促进内含物形成。与突触结合蛋白-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的相互作用更强。体外实验表明，SIAH-2使α-突触核蛋白单泛素化。SIAH蛋白可能在内含物形成中起作用的进一步证据来自于在帕金森病患者路易小体中发现SIAH免疫反应性。
