C-terminal truncated α-synuclein fibrils contain strongly twisted β-sheets

Aditya Iyer, Steven Joop Roeters, Vladimir Kogan, Sander Woutersen, Mireille M A E Claessens, Vinod Subramaniam

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Abstract

C-terminal truncations of monomeric wild-type alpha synuclein (henceforth WT-αS) have been shown to enhance the formation of amyloid aggregates both in vivo and in vitro and have been associated with accelerated progression of Parkinson's disease. The correlation with PD may not solely be influenced by faster aggregation, but also from the effect the deletion of C-terminal residues has on which fibril polymorphs are preferentially formed. Considering that different polymorphs are known to result in distinct pathologies, it is important to understand how these truncations affect the organization of αS into fibrils. Here we present high resolution microscopy and advanced vibrational spectroscopy studies that indicate that the C-terminal truncation variant of αS, lacking residues 109-140 (henceforth referred to as 1-108-αS), forms amyloid fibrils with a distinct structure and morphology. The 1-108-αS fibrils have a unique negative circular dichroism band at ∼230 nm, a feature that differs from the canonical ∼218 nm band usually observed for amyloid fibrils. We show that 1-108-αS fibrils consist of strongly twisted β-sheets with an increased inter-β-sheet distance and a higher solvent exposure than WT-αS fibrils, which is also indicated by the pronounced differences in the 1D-IR (FTIR), 2D-IR and vibrational circular dichroism spectra. As a result of their distinct β-sheet structure 1-108-αS fibrils resist incorporation of WT-αS monomers.

Original languageEnglish
Pages (from-to)15392-15400
Number of pages9
JournalJournal of the American Chemical Society
Volume139
Issue number43
DOIs
Publication statusPublished - 2-Oct-2017
Externally publishedYes

Keywords

  • Journal Article

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