Project Summary This proposal outlines a five-year career development program aimed at promoting the principal investigator to research independence as a clinician scientist in basic and translational neuroscience, with specialization in cell type-specific mechanisms that regulate neuronal autophagy and modify proteotoxicity in Parkinson disease (PD). Applicant: The applicant has completed M.D. and Ph.D. degrees, residency training in neurology, and fellowship training in PD and movement disorders. He has previous experience in neuroscience research using cell and mouse models to study autophagy in spinobulbar muscular atrophy. His career development plan is designed to focus his research on PD pathogenesis and advance his knowledge in bioinformatics, CRISPR gene editing and high-throughput screening, and advanced imaging techniques. In so doing, the training plan outlined herein builds upon his prior training to achieve research independence. He will benefit from continual mentor engagement, regular meetings and ongoing collaborations. He will learn additional research techniques through formal coursework, workshops, and national meetings. These training mechanisms will provide the applicant with the scientific and conceptual skillset necessary for an independent career in neurodegenerative research. Research Plan: PD is a progressive neurodegenerative disorder marked by motor and non-motor/multi-systemic symptoms that lead to profound disability. There is no effective disease-modifying therapy currently available. Neurodegeneration in PD relates to toxic aggregation of ⍺-synuclein, and mounting evidence shows that ⍺- synuclein can be degraded through the conserved pathway of autophagy. However, current methods to modulate autophagy fail to confer neuroprotective effects in patients. In recently published work, the applicant identified MTMR5 (myotubularin-related phosphatase 5, encoded by the SBF1 transcript) as a potent neuronal autophagy suppressor in neurons. MTMR5 knockdown enhances the sensitivity of neurons to induction of autophagy, and accelerates the degradation of multiple autophagy substrates, including disease-associated and aggregate- prone proteins. In line with this, this proposal will test the central hypothesis that reducing MTMR5 in neurons augments autophagic clearance of ⍺-synuclein and reduces ⍺-synuclein-related neuronal death. The applicant will use human induced pluripotent stem cells (iPSCs) to determine if manipulating SBF1/MTMR5 enhances ⍺- synuclein turnover via autophagy (Aim 1) and modifies ⍺-synuclein proteotoxicity (Aim 2). He will also employ unbiased, genome-wide CRISPR-based screens to uncover key factors regulating MTMR5 in neurons (Aim 3). Collectively, these studies establish a novel research platform focusing on neuronal autophagy, myotubularin biology, and therapy design in PD and related neurodegenerative disorders.