α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation

被引：143

作者：

Wang, Shijun ^{[1
,2
]}

Chu, Chun-Hsien ^{[2
]}

Stewart, Tessandra ^{[1
]}

Ginghina, Carmen ^{[1
]}

Wang, Yifei ^{[3
,4
]}

Nie, Hui ^{[2
]}

Guo, Mingri ^{[2
]}

Wilson, Belinda ^{[2
]}

Hong, Jau-Shyong ^{[2
]}

Zhang, Jing ^{[1
,5
,6
]}

机构：

[1] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA

[2] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA

[3] East Chapel Hill High Sch, Chapel Hill, NC 27514 USA

[4] Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27599 USA

[5] Peking Univ, Hosp 3, Dept Pathol, Beijing 100191, Peoples R China

[6] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Beijing 100191, Peoples R China

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 15期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

alpha-Synuclein; microglial chemotaxis; neuroinflammation; Lyn; hydrogen peroxide; PARKINSONS-DISEASE; REDOX SENSOR; IN-VITRO; ACTIVATION; INFLAMMATION; INHIBITION; NEUTROPHILS; CLEARANCE; LEUKOCYTE; NEURONS;

D O I：

10.1073/pnas.1417883112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Malformed alpha-Synuclein (alpha-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in alpha-synucleinopathies, such as Parkinson's disease. The mechanisms by which alpha-syn aggregates activate and recruit microglia remain unclear, however. Here we show that alpha-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 alpha-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 alpha-syn-mediated microglial migration reaches beyond Parkinson's disease.

引用

页码：E1926 / E1935

页数：10

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