Trehalose-Induced Structural Transition Accelerates Aggregation of α-Synuclein

Fibrillation of alpha-synuclein proceeds through distinct stages, with oligomers combining to form the seed or the nucleus, followed by exponential and saturation phases. Osmolytes are considered to act as protein stabilizers by virtue of their ability to inhibit protein aggregation. Trehalose, a non-reducing disaccharide which is conventionally used as a stabilizer, was found to order alpha-synuclein, a natively disordered protein, into a non-native conformation such that the protein folding pathway is driven towards aggregation. Thus, by ordering the pathway intermediates, the osmolyte trehalose exerts variable effect on an intrinsically disordered protein when compared with its effect on natively folded proteins.