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

The presence of intracellular filamentous alpha-synuclein (alpha S) aggregates is a common feature in Parkinson's disease. Recombinant expressed and purified human alpha S is also capable of forming fibrils in vitro. Many studies have shown that solution conditions heavily influence alpha S fibrillation kinetics, fibril structure, and morphology that exhibit differential biological effects. Nevertheless, the alpha S ensemble structure in various solution conditions is not well characterized; furthermore, how the initial solution ensemble structures impact alpha S 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 alpha S in the presence or absence of a 150 mM sodium chloride (NaCl) solution, where two polymorphs of alpha S were demonstrated in previous studies. Our data show that alpha S exhibits distinct conformations and fibrillation kinetics in these two solutions. alpha S 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 alpha S 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.