Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds

Aggregation of alpha-synuclein (alpha S) into oligomers is critically involved in the pathogenesis of Parkinson's disease (PD). Using confocal single-molecule fluorescence spectroscopy, we have studied the effects of 14 naturally-occurring polyphenolic compounds and black tea extract on alpha S oligomer formation. We found that a selected group of polyphenols exhibited potent dose-dependent inhibitory activity on alpha S aggregation. Moreover, they were also capable of robustly disaggregating pre-formed alpha S oligomers. Based upon structure-activity analysis, we propose that the key molecular scaffold most effective in inhibiting and destabilizing self-assembly by alpha S requires: (i) aromatic elements for binding to the alpha S monomer/oligomer and (ii) vicinal hydroxyl groups present on a single phenyl ring. These findings may guide the design of novel therapeutic drugs in PD. Structured summary of protein interactions: Alpha-synuclein binds to Alpha-synuclein by biophysical (View Interaction 1, 2) (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.