Feb 17, 2021 – NMR Topical Group Meeting

Amyloid fibril formation and propagation of α-Synuclein (αS) is associated with the progression of multiple neurodegenerative diseases, including Parkinson’s Disease. Cell-to-cell spread of αS fibrils is thought to contribute to disease progression, which leads to “seeding” or templated misfolding endogenous αS monomer through processes such as templated elongation and secondary nucleation. The molecular level details of these seeding mechanisms and the interactions that drive the aggregation process are not fully understood, but will be critical in not only fully understanding the process of seeding but also in identifying potential avenues of therapeutic disruption. In this talk, I will describe some of our recent efforts to characterize the interactions between monomeric αS and αS amyloid fibrils using a combination of solution NMR and solid-state NMR techniques. I will describe how combining NMR measurements of relaxation, exchange, and water accessibility with other biophysical measurements of protein aggregation and cell toxicity has led to the identification of a common aggregate binding site on αS monomers, as well as the role that dynamics can play in the ability of amyloid fibrils to template aggregation.