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

Shijun Wang, Chun Hsien Chu, Tessandra Stewart, Carmen Ginghina, Yifei Wang, Hui Nie, Mingri Guo, Belinda Wilson, Jau Shyong Hong, Jing Zhang

Research output: Contribution to journalArticlepeer-review

125 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E1926-E1935
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number15
DOIs
Publication statusPublished - 2015 Apr 14

All Science Journal Classification (ASJC) codes

  • General

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