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NIH Research Festival

September 23 – 25, 2024

Insights into α-Synuclein Amyloid Formation: Effect of N- and C-terminal Truncations at the Residue-level

Authors

  • RP McGlinchey
  • X Ni
  • J Jiang
  • JC Lee

Abstract

The generation of α-synuclein (α-syn) truncations from post-translational processing plays a significant role in the pathogenesis of Parkinson’s disease (PD). In this work, we have examined two C-terminally truncated acetylated (Ac) α-syn (Ac1–122 and Ac1–103), and four N-terminally truncated α-syn (14‒140, 36‒140, 41–140, and 66–140) variants. Strikingly, the removal of the acidic C-terminal tail facilitated faster aggregation and efficiently seeded the full-length protein. While N-terminal residue deletions had varying effects on aggregation, only 14‒140 were competent seeds. The fibril structure of 41‒140 solved by cryoelectron microscopy revealed a novel amyloid structure composed of two asymmetric protofilaments, which in turn explains the incompatibility to cross-seed the full-length protein. While one protomer resembles the bent β-arch kernel, comprised of residues E46‒K96 as in the other structures, the other protomer is folded into an extended β-hairpin conformation with fewer residues (E61‒D98). Although the two C-terminal truncations revealed modest changes when compared to full-length protein, all four fibril structures revealed a salt bridge involving Lys80. Thus, motivating our mutational study to identify essential charge residues that dictate aggregation propensity of a PD-related truncation (66–140). Importantly, charge neutralization effects were site-dependent, arguing for the presence of specific electrostatic interactions and potential salt bridge formation, impacting both nucleation and fibril propagation processes of aggregation. Key electrostatic interactions involved residues E83, K80, K96 and K97. Moreover, fibril morphology and homogeneity were altered in both E83A and K80A mutants. Together, these results offer new insights into the role of truncations in α-syn fibril polymorphism at the residue level.

Scientific Focus Area: Biomedical Engineering and Biophysics

This page was last updated on Tuesday, August 6, 2024

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Current Research Festival

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