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Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):E1926-35. doi: 10.1073/pnas.1417883112. Epub 2015 Mar 30.

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

Author information

1
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;
2
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
3
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104;
4
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.
5
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.

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.

KEYWORDS:

Lyn; hydrogen peroxide; microglial chemotaxis; neuroinflammation; α-Synuclein

PMID:
25825709
PMCID:
PMC4403145
DOI:
10.1073/pnas.1417883112
[Indexed for MEDLINE]
Free PMC Article

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