LRRK2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis

Abstract

Parkinsons Disease (PD) is a progressive, neurodegenerative disorder characterised by motor and non-motor symptoms. Emerging evidence suggests a link between PD and gastrointestinal dysfunction. Constipation is frequently observed years prior to development of motor dysfunction in PD, and people with inflammatory bowel disease (IBD) are more likely to develop PD. Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) account for approximately 1% of all PD cases and are associated with increased risk for IBD. Among them, LRRK2 Gly2019Ser (G2019S), located within the kinase domain, is the most common PD-associated mutation and increases kinase activity. It is unknown how LRRK2 mutation affects susceptibility to intestinal inflammation or pathogenesis of PD. Using single cell RNA sequencing (scRNAseq), we demonstrate that LRRK2 G2019S mutation promotes a dysregulated gene profile, especially within neutrophil, monocyte and {gamma}{delta} 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. We also uncover cell-intrinsic functional defects in LRRK2 G2019S neutrophils, including increased chemotaxis, degranulation and neutrophil extracellular traps (NETosis) 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. Understanding the early perturbations driven by the LRRK2 G2019S mutation in gastrointestinal pathology may facilitate the development of biomarkers for early diagnosis and intervention in PD.