The Parkinson’s Disease-associated mutation LRRK2 G2019S impacts neutrophil effector functions and the response to intestinal infection in mice 9106

Abstract Description Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder. Emerging evidence suggests involvement of the gut-brain axis and the immune system in PD pathogenesis. The leucine-rich repeat kinase 2 gene (LRRK2) is expressed in immune cells and mutations in this gene are associated with increased risk for PD and for Inflammatory Bowel Disease. LRRK2 Gly2019Ser (G2019S), located within the kinase domain, is the most common PD-associated mutation and increases LRRK2 kinase activity. Using single cell RNA sequencing, we demonstrate that LRRK2 G2019S mutation promotes a dysregulated gene expression profile, especially within neutrophil, monocyte and γδ T cell populations, following Citrobacter rodentium infection in mice. Transcriptionally, LRRK2 G2019S neutrophils have a greater pro- inflammatory type I and II IFN response compared to those of WT mice. This is accompanied by an increase in neutrophil numbers in the lamina propria in LRRK2 G2019S mice during infection. We also uncover cell-intrinsic functional defects in LRRK2 G2019S neutrophils, including increased chemotaxis, degranulation and neutrophil extracellular trap formation. Increased neutrophil infiltration is associated with an upregulation in Th17 immune responses, which may together contribute to the observed increase in colon pathology during infection. These findings increase our understanding of the role of PD-associated genes in immune cells and their contribution to immune dysregulation. Funding Sources Supported by CIHR, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Aligning Science Across Parkinson’s (ASAP) initiative. Topic Categories Neuroimmunology (NEUR)