Research Project
10284435
Project Summary Previous findings suggest a biological link between Inflammatory bowel disease (IBD) and Parkinson?s Disease (PD). However, the exact mechanism potentially linking gut inflammation to PD progression remains unknown. Interestingly, PD and IBD are both linked to mutations in the LRRK2 gene; specifically, recent genetic analyses led by Project 3?s PI Peter linked the LRRK2 variant N2081D to increased risk for both PD and IBD. It is however unknown whether the LRRK2N2081D variation plays a role in the development of these progressive disorders. Accordingly, the overall aim of this project is to examine the role of LRRK2 in ?-synuclein-induced pathologies in gut tissue and their potential spread to brain. The approach is based on assessing the effects of inducing ?- synuclein overexpression in lymphocytes and ileum/colon enteric neurons of LRRK2N2081D mutants and their wild- type counterparts. To attain cell specificity, we will employ optimized (adeno-associated) viral delivery systems that enable efficient systemic and organ-specific gene transduction. We will employ these cutting-edge viral techniques to induce systemic ?-synuclein overexpression in lymphocytes and local overexpression in ileum/colon enteric neurons in LRRK2N2081D mutants and wild-type mice. We will assess gut motility, motor deficits, stool-based biomarkers, gut microbiome composition, as well as endogenous mouse ?-synuclein aggregation and spreading. Accordingly, our Specific Aims are (1) to assess the impact of LRRK2N2081D variants on systemic lymphocytes vs. local ileum /colon enteric neuron pS129-?-syn aggregation and pathology; (2) to examine the impact of LRRK2N2081D variants on stool-based biomarkers and gut microbiome composition upon lymphocytic and enteric ?-synuclein overexpression; (3) to examine the impact of LRRK2N2081D variants on Parkinsonian behavioral and cellular phenotypes upon lymphocytic and enteric ?-synuclein overexpression. We expect greater motor deterioration and ?-synuclein aggregation in the brain of LRRK2 N2081D mutants upon enteric ?-synuclein transfection. On the other hand, we expect attenuated brain pS129-?-syn invasion upon lymphocytic ?-synuclein transfection. The outcome of these studies may reveal novel opportunities for early interventions in the course of PD progression.
