Impact of the α-Synuclein Initial Ensemble Structure on Fibrillation Pathways and Kinetics.

Abstract

The presence of intracellular filamentous α-synuclein (αS) aggregates is a common feature in Parkinson's disease. Recombinant expressed and purified human αS is also capable of forming fibrils in vitro. Many studies have shown that solution conditions heavily influence αS fibrillation kinetics, fibril structure, and morphology that exhibit differential biological effects. Nevertheless, the αS ensemble structure in various solution conditions is not well characterized; furthermore, how the initial solution ensemble structures impact αS assembly kinetics and pathways that result in diverse fibril structure and morphology remains elusive. Here, we mainly employed NMR spectroscopy to characterize the initial ensemble structure of αS in the presence or absence of a 150 mM sodium chloride (NaCl) solution, where two polymorphs of αS were demonstrated in previous studies. Our data show that αS exhibits distinct conformations and fibrillation kinetics in these two solutions. αS adopts a more compact and rigid ensemble structure that has faster fibrillation kinetics in the absence of NaCl. On the basis of the ensemble structure and dynamics, we proposed a possible molecular mechanism in which αS forms different polymorphs under these two conditions. Our results provide novel insights into how the initial conformation impacts fibrillation pathways and kinetics, suggesting that a microenvironment can be used to regulate the intrinsically disordered proteins assembly.