Parkinson's disease is a devastating neurodegenerative disorder in which patients experience motor and cognitive symptoms. The protein alpha-synuclein is present in the hallmark brain pathology of Parkinson's disease, yet the role of alpha-synuclein in the disease process remains unclear. Growing evidence suggests that toxic alpha-synuclein proteins may appear first in neurons of the digestive tract, and then spread to infect vulnerable brain areas in a way similar to prion proteins. This "gut-to-brain" hypothesis of Parkinson's disease is consistent with environmental exposures, potentially from diet or lifestyle, deployment, or occupational exposures, that may initiate the disease process in the gut. Yet, the effects of gut-derived alpha-synuclein on cognitive ability, the mechanisms by which alpha-synuclein spreads, and how novel therapies can target alpha-synuclein-induced cognitive decline all remain unknown. Rodent models of "gut-to-brain" alpha-synuclein spreading are time-consuming and labor-intensive to work with, and are not suitable for large-scale experimentation. Therefore, my lab is using the small nematode worm, Caenorhabditis elegans (C. elegans), which will allow for rapid, systematic testing of potential disease mechanisms and treatments. C. elegans are able to learn and remember patterns in their environment, and we will use established learning and memory assays to test cognitive function in our new C. elegans models of "gut-to-brain" alpha-synuclein spread. We propose to identify key learning and memory regulators that are disrupted by alpha-synuclein, screen highly conserved genes to determine if they facilitate alpha-synuclein spreading, and test U.S. Food and Drug Administration-approved drugs and dietary supplements to identify those that improve cognitive function in our models. This work will provide the first account of how "gut-to-brain" spreading of alpha-synuclein affects cognition, and will offer new targets for halting this neurotoxic spread, thereby advancing the field of neurotoxin exposure Parkinson's research. In addition, this study may identify new potential therapies that can quickly be repurposed for the treatment of Parkinson’s patients with cognitive decline, thereby advancing treatment-related Parkinson's research as well as patient care.