Recent advances in the structural biology of disease relevant α-synuclein fibrils have revealed a variety of structures, yet little is known about the process of fibril aggregate formation. Characterization of intermediate species that form during aggregation is crucial, however this has proven very challenging due to their transient nature, heterogeneity and low population. Here we investigate the aggregation of membrane bound α-synuclein. Through a combination of kinetic and structural studies we identify key time points in the aggregation process, that enable targeted isolation of pre-fibrillar and early fibrillar intermediates. By using solid-state NMR, we show the gradual build-up of structural features in an α-synuclein fibril filament, revealing a segmental folding process. We identify distinct membrane binding domains in α-synuclein aggregates, and the combined data is used to present a comprehensive mechanism of the folding of α-synuclein on lipid membranes. An outlook on interactions with small molecules will be given.

Molecular mechanism of αS filament folding on membranes

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.