Investigating the relationship of genetic, microbial, and intestinal inflammatory biomarkers in PD pathogenesis

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Currently, no available therapies alter the underlying neurodegenerative process, and only symptomatic therapies can improve patient quality of life. This may be in part attributable to the fact that different PD subtypes require distinct therapies, indicating a substantial unmet need for more effective personalized therapies that are based on disease etiology. A combination of genetic and inflammatory biomarkers may offer an avenue toward the dissecting PD heterogeneity. There is growing appreciation for the role of chronic inflammation in pathogenesis of PD. Specifically, an increased incidence of PD in patients with inflammatory bowel disease (IBD), a chronic disease of the gut, has been reported world-wide. Our prior work strongly implicated coding PD-related LRRK2 mutations in the pathogenesis of IBD. We also showed that selective LRRK2 inhibitors have ameliorated experimental colitis and reduced inflammatory cytokine TNF-α levels, a hallmark of IBD-associated inflammation, in dendritic cells of IBD patients. The link between intestinal inflammation and PD is also endorsed by elevated markers of intestinal inflammation and pro-inflammatory gut microbiota composition in PD patients, suggesting that dysregulated signaling pathways of the gut immune system could explain the susceptibility to certain subtypes of PD. However, even though reducing inflammatory processes has been suggested as promising interventional goal for PD, no causal biological pathways have been identified to allow for developing novel, or repurposing existing, drug targets. Therefore, the goal of this study is to detect to what extent intestinal inflammation contributes to the development of PD and identify subtypes of PD based on the levels of genetic susceptibility to intestinal immune dysregulation. Our specific aims are: 1) To determine the relationship between intestinal biomarkers and gut microbiome diversity in patients with PD, IBD or controls by comparing fecal calprotectin, a sensitive marker of intestinal inflammation, and stool bacterial diversity between the disease and control groups; 2) Interrogate α-synuclein levels, LRRK2 expression and LRRK2-mediated phosphorylation of target protein in the intestinal tissue of patients with IBD, PD and controls, and 3) Characterize PD patients with high genetically-determined inflammatory burden in terms of their age of onset, motor and non-motor symptoms, disease progression, response to drugs, and comorbidities using polygenic risk scores (PRS) for various intestinal inflammatory conditions calculated in large existing PD datasets. We will identify the biological pathways shared between PD and immune-mediated diseases. The proposed studies will help better understand the role of intestinal inflammation in PD pathogenesis. In addition, they will help establish an infrastructure for successful patient recruitment and sample collection and formalize new collaborative directions to support large scale studies of P50 aimed at identifying early biomarkers of PD risk, determining PD subtypes, and developing new therapeutic targets.