PROTEOMIC MAPPING OF PATHOLOGICAL INTERACTIONS ACROSS THE SYNUCLEINOPATHY BRAIN

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Summary Statement The cellular processes responsible for Lewy pathology (LP) formation, maturation, and clearance in human disease tissues remain unknown in part because a lack of techniques available to capture LP interactions in the intact cellular environment. The long-term goal is to determine the core-cellular processes responsible for LP in the human brain and find therapeutic targets to develop disease modifying treatments for synucleinopathy. The objective of this proposal is to determine the role of LP interactions in the initiation and progression of synucleinopathies. The central hypothesis is that core molecular LP interactions are the major determinants of clinical synucleinopathies phenotypes and disease progression. Our rationale for the proposed studies is that determining LP interactions across the neuroaxis of the diseased brain will reveal those core pathological processes responsible for human synucleinopathies and offer a concrete molecular description concerning how those processes define, distinguish, and treat clinical synucleinopathies. The central hypothesis will be tested in two specific aims: 1) Determine LP interactions in the human synucleinopathy brain; 2) Investigate LP interactions across the neuroaxis of a rodent brain as synucleinopathy develops. We will test these aims by using our innovative in situ proximity labeling technique that overcomes previous technical limitations, to provide a clear molecular understanding of LP. The proposed research is significant because it will provide a detailed understanding of LP interactions that should be targets for future disease modifying therapeutics. The expected outcome of the proposed research is to provide the field with an unbiased account of LP interactions in the human diseased brain and in models of synucleinopathy. These results will have an immediate positive impact because they will provide a “big picture” cellular/molecular understanding of human synucleinopathies that is currently unavailable but crucial for progress in the field