Elucidating the Role of LRRK2 Kinase Activity in the Innate Immune System

Mutations in LRRK2 are linked to three distinct diseases: Parkinson's disease (PD), Crohn's disease, and leprosy. The main pathogenic variant of LRRK2 associated with PD is the p.G2019S mutant, which causes increased kinase activity. Recently, a role for LRRK2 has been implicated in the immune system; however, the exact contribution of the kinase activity in this function remains unknown. We have used mice with a Lrrk2 kinase-dead mutation and three distinct infection paradigms to investigate this role. We demonstrated that in the context of two systemic infection models, Lrrk2 kinase is not required for the host's immune response to control virulent pathogens and may in fact be protective in certain paradigms. Additionally, we have shown that Lrrk2 seems to function predominantly in the periphery rather than the brain, and that the p.G2019S mutation confers a gain-of-function. Taken together, these data will provide important insights into LRRK2 biology and PD pathogenesis.