Impact of DSS Induced Intestinal Barrier Dysfunction on Parkinsons Disease Progression in a Mouse Model of Parkinsons Disease

Parkinsons Disease (PD) is the second most common neurodegenerative disease associated with aging in which patients suffer from neuroinflammation and substantia nigra dopaminergic cell loss. An estimated 99.7% of PD patients also exhibit non motor symptoms such as gastrointestinal (GI) dysfunction, olfactory dysfunction, depression, and sleep disorders which precede motor symptoms by years. PD patients also display a dysregulated microbiome and an increase in intestinal and blood brain barrier permeability. From this perspective, the early appearance of GI dysfunction in PD might support a role of leaky gut and gut derived toxin exposure in the pathogenesis of PD. Similarly, the role of intestinal permeability and the release of endotoxins, such as lipopolysaccharide (LPS) and their contribution to neuroinflammation is still uncertain. The objective of this project was to observe if leaky gut derived microbial products, especially LPS, would promote or worsen PD like pathology and behavior in alpha synuclein overexpressing (ASO) PD mouse model. We used dextran sulfate sodium (DSS) to drive gut leakiness in the Thy1 ASO genetic mouse model to study whether exposure to gut derived products promotes/worsens neuroinflammation, and PD like pathology and behavior. The outcome measures of the project include intestinal permeability and behavioral testing, western blot analysis, ELISA for inflammation markers and cytokines, brain microglia immunostaining, and 16s rRNA gene amplicon sequencing for microbiota. Data from these studies will result in a new understanding of potential mechanisms of microglial activation through gut derived microbial products resulting from increased intestinal permeability.