Synuclein is most well-known for its involvement in the etiology of Parkinsonâs disease where Î±-synuclein amyloid fibrils are found in Lewy bodies, a histopathological hallmark. Membrane association of Î±-synuclein is associated with its biological function and implicated in pathogenesis. Upon membrane association, Î±-synuclein adopts an Î±-helical structure, whereas in solution, the protein is disordered. In a disease state, Î²-sheet rich, amyloid fibrils of aggregated Î±-synuclein accumulate in the cytosol. In this work, we aim to understand how amyloid formation is influenced by lipids and in turn, how the protein aggregation process may lead to deleterious Î±-synuclein interactions with membranes. We are especially interested in the ability of Î±-synuclein to sense and generate membrane curvature, which could have both functional and dysfunctional consequences. Building upon the fundamental understanding of Î±-synucleinâlipid interactions, we are developing Raman microspectroscopy to study protein conformational dynamics and aggregation in cells. This powerful approach reports on protein secondary structural changes, allowing us to identify whether the protein has adopted a Î²-sheet rich form, indicative of amyloid structure, as a function of its spatial location. In this talk, I will present our latest results on (1) membrane fluidity and curvature sensing by Î±-synuclein, (2) Raman spectroscopic characterization of Î±-synuclein amyloid formation, and (3) cellular studies of Î±-synuclein. Through our work, we are developing a chemical understanding in how specific biomolecular interactions and cellular environments modulate Î±-synuclein structure and aggregation propensity.
Jennifer Lee (NIH)