Abstract
LRRK2 G2019S is the most prevalent variant associated with Parkinson's disease (PD), found in 1-3% of sporadic and 4-8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S carriers have an increased risk of cancers including colorectal cancer. However, the underlying mechanisms of the positive correlation between LRRK2-G2019S and colorectal cancer remain unknown. Using a mouse model of colitis-associated cancer (CAC) and LRRK2 G2019S knockin (KI) mice, here we report that LRRK2 G2019S promotes the pathogenesis of colon cancer as evidenced by increased tumor number and tumor size in LRRK2 G2019S KI mice. LRRK2 G2019S promoted intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, we found that LRRK2 G2019S KI mice are more susceptible to dextran sulfate sodium (DSS)-induced colitis. Suppressing the kinase activity of LRRK2 ameliorated the severity of colitis in both LRRK2 G2019S KI and WT mice. At the molecular level, our investigation unveiled that LRRK2 G2019S promotes the production of reactive oxygen species, triggers inflammasome activation, and induces cell necrosis in the gut epithelium in a mouse model of colitis. Collectively, our data provide direct evidence that gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, implicating LRRK2 as a potential target in colon cancer patients with hyper LRRK2 kinase activity.