Wang Shijun, Chu Chun-Hsien, Stewart Tessandra, Ginghina Carmen, Wang Yifei, Nie Hui, Guo Mingri, Wilson Belinda, Hong Jau-Shyong, Zhang Jing
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104; Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):E1926-35. doi: 10.1073/pnas.1417883112. Epub 2015 Mar 30.
Malformed α-Synuclein (α-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in α-synucleinopathies, such as Parkinson's disease. The mechanisms by which α-syn aggregates activate and recruit microglia remain unclear, however. Here we show that α-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 α-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 α-syn-mediated microglial migration reaches beyond Parkinson's disease.
神经元中畸形的α-突触核蛋白（α-syn）聚集体释放到细胞外空间，激活小胶质细胞，引发慢性神经炎症，进而加剧α-突触核蛋白病（如帕金森病）中的神经元损伤。然而，α-syn聚集体激活并募集小胶质细胞的机制尚不清楚。在此，我们表明α-syn聚集体作为趋化因子，引导小胶质细胞趋向受损神经元。此外，我们描述了小胶质细胞这种定向迁移的潜在机制。具体而言，当α-syn与整合素CD11b结合时会发生趋化作用，导致NADPH氧化酶产生过氧化氢（H2O2）。H2O2通过一种过程直接吸引小胶质细胞，在此过程中，细胞外产生的H2O2扩散到细胞质中，酪氨酸蛋白激酶Lyn在感知到小胶质细胞内H2O2浓度变化后，使F-肌动蛋白相关蛋白皮质肌动蛋白磷酸化。最后，磷酸化的皮质肌动蛋白介导肌动蛋白细胞骨架重排并促进细胞定向迁移。鉴于α-syn介导的小胶质细胞迁移不仅限于帕金森病，这些发现具有重要意义。
