Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 15, Pages E1926-E1935Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1417883112
Keywords
alpha-Synuclein; microglial chemotaxis; neuroinflammation; Lyn; hydrogen peroxide
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Funding
- NIEHS
- National Institutes of Health [R01 ES019277, R01 ES016873]
- National Natural Science Foundation of China [81129018]
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Malformed alpha-Synuclein (alpha-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in alpha-synucleinopathies, such as Parkinson's disease. The mechanisms by which alpha-syn aggregates activate and recruit microglia remain unclear, however. Here we show that alpha-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 alpha-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 alpha-syn-mediated microglial migration reaches beyond Parkinson's disease.
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