Abstract:  

Motor impairment in Parkinson’s disease is associated with accumulation of aggregates of the protein α-synuclein 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 before irreversible neurodegeneration occurs in the brain. However, effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut and spreads to the brain. Enteroendocrine cells bordering the gut lumen may be the source of intestinal α-synuclein, as they natively express this protein. These cells are constantly exposed to gut bacteria and their metabolites in the gut microbiome, and they also synapse with vagal neurons, which innervate the gut and brain. Through this connection, Parkinson’s disease pathology may originate in the gut and spread to the brain over time. 

In my thesis work, I dissected a gut microbial metabolite-driven mechanism likely involved in disease pathogenesis and identified diet-derived inhibitors of the pathogenic process. Specifically, I observed that nitrite—produced via nitrate respiration by Enterobacteriaceae—is responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. The proposed pathway was found to drive the aggregation of α-synuclein in enteroendocrine cells (in which this protein is natively expressed) as well as in complex fecal bacterial consortia. I also evaluated diet-derived polyphenols dihydrocaffeic acid and caffeic acid—abundant in a Mediterranean diet associated with decreased Parksinon’s disease risk and severity—as inhibitors of α-synuclein aggregation that limit dopamine oxidation. More recently, I made progress towards tracking α-synuclein aggregation and migration in real time via non-invasive bioluminescence-based reporters. Overall, the factors revealed to be involved in disease onset in the gut are foundational for unlocking new avenues for targeted therapeutics to treat Parkinson’s disease, particularly in the context of functional foods that may be used to reshape the gut environment.