Project 452619

Alpha-Synuclein (a-syn) is a key factor in Parkinson's disease (PD) and other neurodegenerative disorders known collectively as synucleinopathies. The main pathology common to these brain disorders is a progressive accumulation of sticky deposits of a-syn in the brain and in the peripheral nervous system of affected individuals. Recent studies suggest that these sticky accumulations of a-syn can be passed from sick neurons to healthy ones, and thereby causing the spread and progression of the disease. In many patients, the earliest appearance of a-syn deposits occurs in the neurons that control gastrointestinal functions, causing symptoms that range in severity from constipation to inflammatory bowel disease. Our recent studies show that therapies designed to reduce a-syn expression in brain hold significant promise to alleviate PD symptoms. Here we will use gene therapy to inhibit expression of gastrointestinal a-syn and evaluate whether this reduces early pathology in the gut and whether it prevents the expected spread of pathology into the brain. Following the treatment, we will assess improvement in gut and motor function, and the presence of neuropathology. Our optimal expectation is that there will be a reduction in movement deficits and less a-syn accumulation in animals that receive the gene therapy. If we are successful, these studies will support the use of a-syn reduction strategies for the treatment of PD.