PROJECT SUMMARY This proposal presents a five-year research career development program focused on the potential role of dysregulated palmitoylation, modification of proteins by the fatty acid palmitate, in the vesicle trafficking defects caused by α-synuclein (αSyn) in Parkinson’s disease (PD). The research and training plan is based upon the candidate’s prior experience in molecular neuroscience, the experienced mentorship of Dr. Dennis Selkoe, and the full institutional support of Brigham and Women’s Hospital (BWH). Completion of the plan is expected to result in important insights into PD biology in addition to the candidate’s career development to an independent laboratory-based investigator. The current lack of disease-modifying therapies for PD, the second most common neurodegenerative disorder, is a large unmet need. The causative role of the neuronal protein αSyn is well appreciated, since mutations in the αSyn gene cause PD and aggregates of αSyn are found in Lewy Bodies, the pathological hallmark of PD. Many studies now suggest that αSyn-dependent disruption of vesicular trafficking plays an important role in the pathogenesis of PD. The proposed research tests the hypothesis that αSyn, which binds to membranes via an amphipathic helix, inhibits palmitoylation of SNARE and SNARE-related proteins, thus disrupting their function in vesicle fusion. Accordingly, the aims are 1) to determine whether a set of SNARE and SNARE-related proteins with PD relevance is dysregulated in animal and iPSC-based models of PD; 2) to determine if enhancement of palmitoylation reduces vesicle accumulation caused by pathologic αSyn; and 3) to determine if enhancement of palmitoylation ameliorates PD-like phenotypes in a mouse model. The career development plan is designed to support the candidate’s goal of becoming an independent investigator with both clinical training in movement disorders and scientific expertise in membrane-protein interactions and vesicle trafficking in human synucleinopathies. Critical to the plan is the unparalleled mentorship of Dr. Selkoe, who has decades of experience in guiding scientists and physician scientists to leadership positions in academia. Formal didactics and seminars on techniques, ethics, and professional skills, combined with an eminent advisory committee add further structure to the career development plan. Finally, the collaborative environment of the Ann Romney Center for Neurologic Diseases at BWH provides numerous material and human resources readily available to the candidate. Taken together, these elements help ensure attainment of the candidate’s goals upon completion of the proposal.