Parkinson’s disease (PD) is a neurodegenerative disease caused by dopaminergic neuronal death in the substantia nigra. Microglia are brain macrophages that continuously survey the microenvironment of the brain to find out and repair brain damage. Although PD associated genes are expressed in microglia, their roles in these cells are largely unknown. The present study revealed that LRRK2, a PD-associated gene, regulates the migration of microglia. LRRK2 was located in ruffles, an actin rich structure of moving cells, when ADP induced microglial movement. In immunoprecipation assay, LRRK2 interacted with focal adhesion kinase (FAK), a protein that regulates the adhesion and migration of cells. LRRK2 and FAK were co-localized with ruffles when microglia actively moved. The overexpression of LRRK2 reduced the phosphorylated FAK levels compared with that of the mock, which suggests that LRRK2 inhibits FAK activation. LRRK2 G2019S, a pathologic LRRK2 mutant, more significantly inhibited the FAK activation and the movement of microglia than non-transgenic LRRK2 did. Furthermore, microglial migration defects were also observed in stab-wounded LRRK2 G2019S TG mice brain. Taken together, these results suggest that LRRK2 suppresses microglial movement by inhibiting FAK activation. Importantly, mutations of LRRK2, such as G2019S, could increase the risk of PD development, since microglia could not properly respond to and repair brain damage.
