Unraveling amyloid formation paths of Parkinson's disease protein α-synuclein triggered by anionic vesicles
AbstractAmyloid formation of the synaptic brain proteinα-synuclein (αS) is related to degeneration of dopaminergic neurons in Parkinson's disease patients.αS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesiclesin vitro. Here we combined circular dichroism, fluorescence and imaging methodsin vitroto characterize the interaction ofαS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), sodium salt) and the consequences of such interactions onαS amyloid formation. We found that lipid head-group chemistry modulatesαS interactions and also affects amyloid fiber formation. During the course of the experiments, we made the unexpected discovery that pre-formedαS oligomers, typically present in a small amount in theαS starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remainingαS monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hiddenαS aggregation pathway may be of importancein vivo.