Leveraging the Gut Microbiota for Mechanistically Informed Therapeutics against Body-First Parkinson's Disease

Although some symptoms of Parkinson's disease can be pharmacologically alleviated, stopping disease progression is not currently possible. Motor impairment in Parkinson's disease is associated with accumulation of aggregates of the protein α-synuclein (α-syn) in dopaminergic neurons in the brain. In some Parkinson's disease cases, these pathogenic aggregates accumulate in the intestinal lining years before motor symptoms manifest. This long prodromal period provides a window of opportunity to detect Parkinson's disease and halt its progression. Specifically, elucidating the factors involved in disease onset in the gut would enable prevention of α-syn aggregation before it spreads to the brain. In this perspective, we highlight discoveries of gut bacteria that induce aggregation of intestinal α-syn as well as efforts to decipher the molecular-level mechanisms by which this process occurs. We also showcase the rationale and potential breadth of applications focused on manipulating the gut microbiome, including biotics, fecal microbiome transplants, and microbial editing. By understanding molecular mechanisms of intestinal α-syn aggregation, the microbiome may be harnessed to control the factors responsible for their pathogenic formation and spread. Such insights will ultimately enable the development of more effective therapeutics for prevention and treatment of Parkinson's disease.