Deciphering LRRK2 pathophysiology in mediating gut-brain axis of PD using novel genetic mouse models

总结

Summary The goal of Project 1 is to test the hypothesis of gut-brain axis and the role of LRRK2 in mediating the gut-brain axis in the pathogenesis of Parkinson’s disease (PD) by using novel LRRK2 genetic mouse models. PD has long been linked to inflammatory bowel disease (IBD), characterized by chronic inflammation and known for two conditions, Crohn’s disease (CD) and ulcerative colitis (UC). Recent identification of LRRK2 variants that increase the risk of both PD and CD has provided genetic basis for the link of the two disorders and raises a question whether they shared the same origin and disease progression. The G2019S of LRRK2 is the most common variant that causes PD with the symptoms indistinguishable from idiopathic PD. Increasing evidence demonstrates a role for LRRK2 in immune response and infection in peripheral immune cells. How disease variants affect LRRK2 functions in inflammation and cause disease, however, remains unknown. The presence of shared PD and IBD risk variants in the LRRK2 gene suggests that LRRK2 signaling pathways act at the interface of these two chronic diseases. Therefore, we hypothesize that investigation of LRRK2 pathophysiology will help elucidate the molecular mechanism underlying intestinal inflammation in IBD and the gut brain axis of PD. PI Peter and Yue recently reported LRRK2 variant N2081D associated with increased risk of CD and PD, consistent with the observations of a higher incidence of PD in IBD patients. To validate the pathogenic role of LRRK2N2081D in CD and PD and test the hypothesis of the gut-brain axis of PD, we established Lrrk2N2081D knock- in (KI) mouse model. We propose to test gut-brain axis for PD pathogenesis and determine the underlying mechanism by characterizing the guts and brain of Lrrk2N2081D and Lrrk2G2019S mice. Specifically, we will (1) investigate progressive inflammation, synucleinopathies and pathologies in the gut and brain following chemically induced colitis; (2) determine cell-type specific disease molecular pathways induced by Lrrk2N2081D and Lrrk2G2019S in mouse guts and brains; (3) determine aberrant kinase activity and specific targets of Lrrk2G2019S and Lrrk2N2081D in mouse guts and brains. The outcome of P20 phase will not only help illuminate the molecular pathways of gut brain axis of PD, but establish the molecular basis and focused hypothesis for the test of LRRK2 targets as disease causative factors in the future P50 application.