文章基本信息

标题：α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation
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作者：Shijun Wang ; Chun-Hsien Chu ; Tessandra Stewart 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：E1926-E1935
DOI：10.1073/pnas.1417883112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance-Synuclein (-syn) aggregates released from neurons activate microglia, leading to chronic neuroinflammation that causes damage to neurons in brains with synucleinopathies, such as Parkinson's disease (PD). However, little is known about the mechanism by which -syn affects microglial activity, especially motility, and why microglia migrate toward the injured neurons and preferentially accumulate along with -syn aggregates in the affected areas, e.g., in the substantia nigra of PD brains. Here we show that neuron-derived -syn aggregates are chemoattractants that direct microglial migration by acting on NADPH oxidase and several specific downstream proteins. Blocking the targets involved in -syn-mediated microglial directional migration may represent a therapeutic strategy to protect against progressive neuronal loss in PD and related synucleinopathies. Malformed -Synuclein (-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in -synucleinopathies, such as Parkinson's disease. The mechanisms by which -syn aggregates activate and recruit microglia remain unclear, however. Here we show that -syn aggregates act as chemoattractants to direct microglia toward damaged neurons. In addition, we describe a mechanism underlying this directional migration of microglia. Specifically, chemotaxis occurs when -syn binds to integrin CD11b, leading to H2O2 production by NADPH oxidase. H2O2 directly attracts microglia via a process in which extracellularly generated H2O2 diffuses into the cytoplasm and tyrosine protein kinase Lyn, phosphorylates the F-actin-associated protein cortactin after sensing changes in the microglial intracellular concentration of H2O2. Finally, phosphorylated cortactin mediates actin cytoskeleton rearrangement and facilitates directional cell migration. These findings have significant implications, given that -syn-mediated microglial migration reaches beyond Parkinson's disease.
关键词：α-Synuclein ; microglial chemotaxis ; neuroinflammation ; Lyn ; hydrogen peroxide