Abstract

The conversion of soluble monomeric α-synuclein into amyloid fibrils is the hallmark of a range of neurological disorders, including Parkinson’s disease. Unlike other amyloidogenic proteins, such as Abeta peptide, involved in Alzheimer’s disease, α-synuclein is surprisingly stable in solution under quiescent conditions and its aggregation is mainly triggered via interaction with surfaces including air/water interface, surfactants, lipid membranes. In fact, we have recently shown that negatively charged lipid vesicles can trigger the aggregation of α-synuclein by enhancing the rate of primary nucleation by up to 3 orders of magnitude. In addition, our results indicate that both the protein:lipid ratio and the chemical properties of the lipids play a role in modulating the kinetics of α-synuclein lipid-induced aggregation. Moreover, the rate of an other surface-induced fibril production process, the auto-catalytic fibril amplification, was shown to be highly sensitive to the solution conditions and to increase by at least 4 orders of magnitude at acidic pHs. In light of these findings, we have developed and applied a series of quiescent experimental protocols to study the effects of intrinsic (disease associated mutations) and extrinsic (homologous proteins and small molecules) factors on the individual microscopic steps of α-synuclein aggregation including, the de novo formation of fibrils, their elongation and their amplification. We find that surface-induced fibril production processes are strongly influenced by these factors.