The generation of α-synuclein (α-syn) truncations from incomplete proteolysis plays a significant role in the pathogenesis of Parkinson’s disease. Here, we report fibril structures of full-length acetylated (Ac) protein (Ac1-140), two C-terminally truncated α-syn (Ac1-122 and Ac1-103), and an N-terminally truncated α-syn (41-140) solved by cryoelectron microscopy. For the C-terminal truncations, both proteins exhibited faster aggregation kinetics and Ac1-103 fibrils efficiently seeded the full length protein, highlighting their importance in pathogenesis. The removal of C-terminal residues resulted in increased fibrillar twist, accompanied by modest conformational changes in a more compact amyloid core. For 41-140, a novel amyloid structure with two asymmetric protofilaments was found. While one protomer resembled the previously characterized bent β-arch kernel, comprised of residues E46-K96, the other protomer is folded into an extended β-hairpin conformation with fewer residues (E61-D98) that does not resemble other reported structures. In stark contrast to the C-terminal truncations, both soluble and fibrillar 41-140 inhibited full-length α-syn aggregation and fibril propagation. Together, these results offer new insights into α-syn fibril polymorphism and the interplay between full-length and its truncations.

Effect of N- and C-terminal truncations on α-synuclein amyloid formation and fibril structure

ACS Spring Meeting 2021

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