ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia

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7. Project Summary/Abstract The goal of this mentored career development award is to facilitate the candidate's transition to independence as a physician-scientist studying molecular mechanisms of neurodegeneration. The candidate is an MD/PhD neurologist with a background in neurodegenerative disease research. The award will help the candidate achieve his short-term goal, to gain research experience in the molecular pathogenesis of Parkinson disease and dementia and facilitate his transition to an investigator with an independent laboratory. The award will also help position the candidate to achieve his long-term goal of becoming a successful and productive physician- scientist and a leader in academic neurology. The environment in which the proposed research will be conducted is outstanding. The candidate's primary mentor, Dr. David Holtzman, is an internationally respected scientist and neurologist with a proven track record of excellence in training junior faculty. The candidate's career development plan also includes structured mentorship from multiple physician-scientists at all stages of seniority and exposure to a rich and supportive faculty, ensuring that the candidate has role models along the full spectrum of the career trajectory. Didactic learning, presentation of work at scientific meetings, and rigorous training in the responsible conduct of research will ensure a balanced development. The proposed research will examine the role of apolipoprotein E (apoE) in regulating the aggregation and pathological spread of alpha synuclein (αSyn), a protein implicated in Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB). The aggregation of αSyn from its native monomer form into oligomers is thought to be toxic and to contribute to neuronal dysfunction. This process is regulated by other proteins including chaperone proteins. Several genetic studies point to the APOE ε4 allele, the strongest genetic risk factor for Alzheimer disease, as a risk factor for developing dementia in PD as well. APOE is and is known to regulate amyloid-beta (Aβ) pathology and individuals with PD often have comorbid αSyn and Aβ pathology, but importantly, the risk effect of APOE in PDD and DLB appears to be independent of Aβ pathology. The goal of this project is to test the hypothesis that apoE isoforms differentially regulate αSyn aggregation by stabilizing a harmful oligomeric intermediate. A secondary hypothesis is that apoE regulates the propagation of pathologic conformations of αSyn from cell to cell in vivo. The proposed experiments are designed to elucidate a potential novel relationship between apoE and αSyn, with the ultimate goal of identifying therapeutic targets that can be leveraged to treat diseases caused by pathologic aggregation of αSyn. This career development award is an ideal mechanism to provide the candidate with valuable research training which will complement his clinical focus in movement disorders and will help develop a skill set for translating basic science discoveries into effective therapies for patients with neurodegenerative diseases.