PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting over 10 million people worldwide and contributes to over $52 billion yearly in US healthcare costs. Despite investigation into mechanisms of α-synuclein (aSyn) misfolding and aggregation leading to neuronal dysfunction and death, the inciting events of the hallmark of PD pathology in humans are not understood. The systemic manifestations of PD have led to the discovery of αsyn pathology in multiple peripheral tissues, including plasma. Understanding the origin of peripheral aSyn pathology is critical to advancing the understanding of PD and to developing early disease-modifying therapies. In preliminary work, antibodies generated against in vitro strains of aSyn are detectable at higher levels in individuals with PD (iwPD), reliably discriminating them from individuals with Dementia with Lewy bodies, when no other differentiating biomarkers exists Furthermore, one of these aSyn strains is elevated in plasma from iwPD who have a reduced rate of cognitive decline. These strains are not reliably detected in cerebrospinal fluid and do not correlate with levels of strain-specific aSyn found in white or red blood cells implicating an alternative peripheral tissue source. The goals of this proposal are 1) to use extracellular vesicles, membrane-bound structures secreted by cells, to identify the tissue source of plasma aSyn strains in an unbiased manner and 2) determine the functional and pathogenic properties of plasma aSyn strains in biochemical assays and a cellular model of PD. In line with the mission of the NINDS, this work has the potential to improve understanding of fundamental mechanisms of PD pathogenesis and to lead to development of treatments that reduce PD morbidity. Dr. George Kannarkat is a driven, highly qualified physician-scientist who is currently an Instructor and participating in the “Remapping Clinical Neuroscience through Translation and Innovation Training” T32 training program at the University of Pennsylvania. He has a proven track record of productivity in basic, translational, and clinical research, particularly with a background in peripheral and immune mechanisms of neurodegeneration. This five-year mentored K08 award including mentorship, formal and self-directed training, and a rigorous research plan will allow him to broaden his skills in 1) large-scale nucleic acid and proteomics analysis, 2) models of synucleinopathy, and 3) manipulation of induced pluripotent stem-cells. With strong institutional support from the numerous resources at the University of Pennsylvania and the mentorship from Dr. Alice Chen-Plotkin (mentor), a world-renowned expert in bioinformatic approaches to identifying biomarkers of neurodegeneration, and his advisory committee, he is well-poised to achieve his goal of being an independent R01-funded physician-scientist studying the interplay of peripheral and central mechanisms, such...