title: α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation.
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.
authors.affiliation: 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;
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chu
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104;
authors.forename: Tessandra
authors.initials: T
authors.lastname: Stewart
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104;
authors.forename: Carmen
authors.initials: C
authors.lastname: Ginghina
authors.affiliation: East Chapel Hill High School, Chapel Hill, NC 27514; Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599; and.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Hui
authors.initials: H
authors.lastname: Nie
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Mingri
authors.initials: M
authors.lastname: Guo
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104; Department of Pathology, Peking University Third Hospital and School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China zhangj@u.washington.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D002630:Chemotactic Factors; D051356:Cortactin; D008562:Membrane Glycoproteins; D016877:Oxidants; D051844:alpha-Synuclein; D006861:Hydrogen Peroxide; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
keywords: Lyn; hydrogen peroxide; microglial chemotaxis; neuroinflammation; α-Synuclein
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