Single-Molecule Study of Synuclein Folding/Fibrillation

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DESCRIPTION (provided by applicant): Alpha-synuclein has been implicated in the pathogenesis of several neurodegenerative disorders including the two most common ones, Alzheimer's disease and Parkinson's disease. Understanding the molecular basis of synuclein misfolding and fibril aggregate formation is an essential step in the prevention and cure of these disorders. The major thrust of the proposed study is to answer questions as to how different protein folded/unfolded conformations contribute to oligomerization, and the subsequent formation of fibrillar aggregates. In addition, the effects of alterations in solvent conditions on the mechanism of synuclein folding and aggregation will be explored. A novel biophysical technique to be employed is single-molecule fluorescence spectroscopy, in particular the recently developed single-pair fluorescence resonance energy transfer (sp-FRET) diffusion method. Single-molecule methods have the advantage of directly probing different structural distributions and dynamic heterogeneity not accessible to standard ensemble methods, and the potential to detect rare protein states that could be the conformational traps that tilt the potential energy landscape towards protein misfolding and aggregation.