title: Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds.
abstract: Aggregation of alpha-synuclein (αS) 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 αS oligomer formation. We found that a selected group of polyphenols exhibited potent dose-dependent inhibitory activity on αS aggregation. Moreover, they were also capable of robustly disaggregating pre-formed αS oligomers. Based upon structure-activity analysis, we propose that the key molecular scaffold most effective in inhibiting and destabilizing self-assembly by αS requires: (i) aromatic elements for binding to the αS 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.
authors: Dept. of Physiology & Biochemistry, University of Malta, Msida MSD 2080, Malta.
authors: Mario
authors: M
authors: Caruana
authors: Tobias
authors: T
authors: Högen
authors: Johannes
authors: J
authors: Levin
authors: Andreas
authors: A
authors: Hillmer
authors: Armin
authors: A
authors: Giese
authors: Neville
authors: N
authors: Vassallo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D044950:Flavanones; D005419:Flavonoids; D007502:Iron Chelating Agents; D010636:Phenols; D059808:Polyphenols; D011994:Recombinant Proteins; D051844:alpha-Synuclein; C006680:baicalein; D047310:Apigenin; D003676:Deferoxamine; C458179:scutellarein; D001205:Ascorbic Acid; D000111:Acetylcysteine