Amyloid at the nanoscale: single molecule and ensemble studies of amyloid-lipid interactions

Misfolding and aggregation of proteins into nanometer-scale fibrillar assemblies is a hallmark of many neurodegenerative diseases. Despite decades of research, the underlying biophysics remains a mystery. A particularly interesting and relevant question is the role of early aggregates in modulating the dynamics of protein nucleation and aggregation, and the mechanism of interactions of these species with lipid membranes. The transient nature, inherent heterogeneity, and low numbers of early stage aggregates necessitate single molecule spectroscopy approaches and other methods that can detect distributions of structures in ensembles.

We have worked extensively on the conformational dynamics and self-assembly of the human intrinsically disordered protein alpha synuclein, involved in the etiology of Parkinson’s disease. In this talk, I will summarize recent work using a broad repertoire of quantitative single molecule and ensemble biophysical techniques to characterize, at nanometer length scales, conformational and morphological details of alpha-synuclein amyloid nanostructures, and their interactions with lipid membranes.