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

ABSTRACT: Malformed ?-Synuclein (?-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in ?-synucleinopathies, such as Parkinson's disease. The mechanisms by which ?-syn aggregates activate and recruit microglia remain unclear, however. Here we show that ?-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 ?-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 ?-syn-mediated microglial migration reaches beyond Parkinson's disease.

SUBMITTER: Wang S 

PROVIDER: S-EPMC4403145 | biostudies-other | 2015 Apr

REPOSITORIES: biostudies-other

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

Wang Shijun S   Chu Chun-Hsien CH   Stewart Tessandra T   Ginghina Carmen C   Wang Yifei Y   Nie Hui H   Guo Mingri M   Wilson Belinda B   Hong Jau-Shyong JS   Zhang Jing J  

Proceedings of the National Academy of Sciences of the United States of America 20150330 15

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 dire  ...[more]