Understanding the role of LRRK2 G2019S-mediated gut-brain axis in the pathogenesis of Parkinson's disease - Project Summary: Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world, with over 1 million Americans currently suffering from PD. The risk of PD increases greatly in people over the age of 65 years. Both genetic and environmental factors are known to contribute to the pathogenesis of PD. Among these, LRRK2-G2019S is the most prevalent, being found in a wide range of ethnic groups and in 1-3% of sporadic and 4-8% of familial PD cases. However, how LRRK2-G2019S promotes the pathogenesis of PD remains largely unknown. Surprisingly, G2019S knockin(KI) mice only develop pre-symptoms of PD, suggesting other triggers are needed for the pathogenesis. We recently reported a crucial role for LRRK2 in the activation of NLRC4 inflammasome and subsequent production of IL-1β. A recent study showed that increased serum levels of IL-1β effectively identified asymptomatic LRRK2-G2019S carriers from noncarriers in humans and higher IL-1β concentration in the serum predicted increased risk for developing PD among the asymptomatic carriers, suggesting that inflammasome activation might play critical roles in PD pathogenesis. Of note, numerous studies have identified pathophysiological changes in the gastrointestinal tract in PD patients preceding the development of motor symptoms. PD patients have higher incidence of gut dysbiosis, and gut dysbiosis promotes PD pathogenesis in animal models. Furthermore, IBD patients have 20–90% higher risk of developing PD. Intriguingly, a recent finding unraveled novel pathogenic LRRK2 variants shared by both IBD and PD, suggesting LRRK2 might bridge the gut-brain axis in PD pathogenesis. We thus hypothesize that second hit-induced LRRK2-mediated intestinal inflammation promotes the PD penetrance in the predisposed LRRK2-G2019S KI model. The objective of our study is to test the “two-hit” model for PD etiology in LRRK2-G2019S KI mice and establish novel PD models through gut-brain axis. Our long-term goal is to understand the underlying mechanisms of the LRRK2-mediated gut-brain axis in the pathogenesis of PD. We will test our hypothesis with two specific aims: Aim 1, Establish a model for investigation of the role of LRRK2-mediated enteric NLRC4 inflammasome activation in the pathogenesis of PD; Aim 2, Establish a model for investigation of the role of LRRK2-mediated colitis in the pathogenesis of PD. Completion of this project will provide novel PD models through gut-brain axis for further understanding of the role of LRRK2- mediated gut-brain axis in the pathogenesis of PD.
