The Influence of Pathogenic Mutations in α-Synuclein on Biophysical and Structural Characteristics of Amyloid Fibrils

Proteinaceous deposits of α-synuclein amyloid fibrils are a hallmark of human disorders including Parkinson's disease. The onset of this disease is also associated with five familial mutations of the gene encoding the protein. However, the mechanistic link between single point mutations and the kinetics of aggregation, biophysical properties of the resulting amyloid fibrils, and an increased risk of disease is still elusive. Here, we demonstrate that the disease-associated mutations of α-synuclein generate different amyloid fibril polymorphs compared to the wild type protein. Remarkably, the α-synuclein variants forming amyloid fibrils of a comparable structure, morphology, and heterogeneity show similar microscopic steps defining the aggregation kinetics. These results demonstrate that a single point mutation can significantly alter the distribution of fibrillar polymorphs in α-synuclein, suggesting that differences in the clinical phenotypes of familial Parkinson's disease could be associated with differences in the mechanism of formation and the structural characteristics of the aggregates.