Enhancing diagnosis of Parkinson's disease and multiple system atrophy via detection of alpha-synuclein seeding activity

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Synucleinopathies such as Parkinson's disease (PD) and multiple systems atrophy (MSA) involve abnormal accumulation of the protein alpha-synuclein (α-syn). Although it has been nearly two centuries since PD was first described, a dearth of biomarkers has greatly impeded progress toward development of disease-modifying treatments and accurate and early diagnosis. This proposal is based on the hypothesis that pathology in these diseases propagates through the brain via a mechanism in which transcellular movement of misfolded α-syn protein aggregates or “seeds” occurs. There is also evidence that pathogenic α-syn has diverse structures in diseases such as PD or MSA, that may underlie the clinical and pathologic differences seen in these synucleinopathies. This proposal utilizes a novel cell-based assay that has been shown to detect and quantify abnormal α-syn seeding activity that differs both biochemically and structurally in brain extracts from patients with PD and MSA. In this project we propose to (1) optimize the ability to detect aggregated forms of α-syn utilizing genetic manipulation of a cell-based sensor, (2) utilize cutting edge molecular and imaging techniques to parse out differences between α-syn in the synucleinopathies MSA and PD, and (3) determine whether α-syn seeding activity in blood components of patient samples can serve as a marker for clinical disease progression. The implications of this work include facilitation of diagnosis and therapeutics for patients with PD and MSA. The applicant is an Assistant Professor in the Department of Neurology at University of Kentucky, who is firmly committed to an academic career as an independent translational scientist in the area of neurodegenerative disease. The proposed training will take advantage of the rich and collaborative environment at the VA, the excellent clinical documentation and records system, and the very relevant patient population affected by these diseases and followed in clinic at the VA: all are factors that are integral and crucial to the success of this proposal. Training will be conducted under the direction of an experienced mentor team. Dr. John Slevin, will be the primary mentor, and has over 40 years of expertise in clinical research in Movement Disorders and holds a Merit Award at the VA in basic science research. Dr. Sidney Whiteheart and Dr. Haining Zhu will serve as co- mentors. They are experts in platelet biochemistry and abnormal protein aggregation, respectively, hold Merit Awards in their fields, and are also faculty in the Department of Molecular and Cellular Biochemistry at University of Kentucky. These mentors have been specially selected to advance the candidate’s knowledge of molecular techniques for investigating aggregated proteins in peripheral fluids of patients with movement disorders. Training during this proposal includes advanced genetic, molecular, and imaging-based techniques for protein amplification and detection, and techniques for isolation and analysis of exosomal and platelet fractions from whole blood. These components will be essential to completing the applicant’s immediate goal of developing a biomarker that can detect and differentiate between synucleinopathies in peripheral samples by utilizing differences in α-syn seeding activity. The comprehensive training program will position the applicant to conduct independent research in the study of novel biomarkers in PD and related neurodegenerative disease.