Unlike Twins: An NMR Comparison of Two α-Synuclein Polymorphs Featuring Different Toxicity

We structurally compare, using solid-state NMR, two different polymorphs of alpha-synuclein which, as established recently, display contrasting biochemical properties, toxicity, and tropism for cells. We show that both forms, which can each be produced as a pure polymorph, are greatly different in secondary structure. While beta-sheets are the dominating secondary structure elements for both polymorphs, they are markedly divergent in terms of number of elements, as well as their distribution. We demonstrate that all identified beta-sheets feature an in-register parallel stacking for both polymorphs. The two forms show a different molecular arrangement in the unit cell and distinct dynamic features, while sharing a highly flexible C-terminal domain. The use of reproducible, well-identified conditions for sample preparation and the recording of identical NMR experiments allows for a direct comparison of the results.