Title: α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation.
Authors: Wang, Shijun; Chu, Chun-Hsien; Stewart, Tessandra; Ginghina, Carmen; Wang, Yifei; Nie, Hui; Guo, Mingri; Wilson, Belinda; Hong, Jau-Shyong; Zhang, Jing
Published In Proc Natl Acad Sci U S A, (2015 Apr 14)
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.
PubMed ID: 25825709
MeSH Terms: Animals; Animals, Newborn; CD11b Antigen/genetics; CD11b Antigen/metabolism; Cell Movement*; Cells, Cultured; Chemotactic Factors/metabolism; Cortactin/metabolism; Hydrogen Peroxide/metabolism*; Hydrogen Peroxide/pharmacology; Immunoblotting; Membrane Glycoproteins/deficiency; Membrane Glycoproteins/genetics; Mice, Inbred C57BL; Mice, Knockout; Microglia/cytology; Microglia/drug effects; Microglia/metabolism*; Microscopy, Confocal; NADPH Oxidase 2; NADPH Oxidases/deficiency; NADPH Oxidases/genetics; Neurons/cytology; Neurons/metabolism; Oxidants/metabolism; Oxidants/pharmacology; Phosphorylation; RNA Interference; Rats; Signal Transduction; alpha-Synuclein/genetics; alpha-Synuclein/metabolism*; alpha-Synuclein/pharmacology; src-Family Kinases/genetics; src-Family Kinases/metabolism*