Rapid anionic micelle-mediated alpha-synuclein fibrillization in vitro.
Parkinson's disease is characterized by the aggregation of alpha-synuclein into filamentous forms within affected neurons of the basal ganglia. Fibrillization of purified recombinant alpha-synuclein is inefficient in vitro but can be enhanced by the addition of various agents including glycosaminoglycans and polycations. Here we report that fatty acids and structurally related anionic detergents greatly accelerate fibrillization of recombinant alpha-synuclein at low micromolar concentrations with lag times as short as 11 min and apparent first order growth rate constants as fast as 10.4 h-1. All detergents and fatty acids were micellar at active concentrations because of an alpha-synuclein-dependent depression of their critical micelle concentrations. Other anionic surfaces, such as those supplied by anionic phospholipid vesicles, also induced alpha-synuclein fibrillization, with resultant filaments originating from their surface. These data suggest that anionic surfaces presented as micelles or vesicles can serve to nucleate alpha-synuclein fibrillization, that this mechanism underlies the inducer activity of anionic surfactants, and that anionic membranes may serve this function in vivo.
D003902:Detergents / Q000494:pharmacology; D019281:Dimerization; D005227:Fatty Acids / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D008823:Micelles; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D010743:Phospholipids / Q000494:pharmacology; D051843:Synucleins; D051844:alpha-Synuclein
D003902:Detergents; D005227:Fatty Acids; D008081:Liposomes; D008823:Micelles; D009419:Nerve Tissue Proteins; D010743:Phospholipids; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein