C-Terminal Truncated α-Synuclein Fibrils Contain Strongly Twisted β-Sheets

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

*Corresponding author for this work

    Research output: Contribution to JournalArticleAcademicpeer-review

    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 (PD). The correlation with PD may not solely be a result of faster aggregation, but also of which fibril polymorphs are preferentially formed when the C-terminal residues are deleted. 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 evidence 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 - 1 Nov 2017

    Funding

    The authors thank Nathalie Schilderink and Kirsten van Leijenhorst-Groener for assistance in protein expression and purification and Prof. Roberta Croce from the VU University Amsterdam and Prof. J. Antoinette Killian from the Utrecht University for access to the CD spectrometer. The authors also thank Dr. Volodymyr Shvadchak for discussions and for providing the polarity-sensitive FE dye. The work presented here is part of a project titled “A Single Molecule View on Protein Aggregation” (No. 127) funded by the Foundation for Fundamental Research on Matter (FOM), now merged with The Netherlands Organisation for Scientific Research (NWO). We also acknowledge support from NanoNextNL, a micro-and nanotechnology consortium of the Government of The Netherlands and 130 partners. S.J.R. and S.W. acknowledge the European Research Council (ERC) for funding through grant 210999 and The Netherlands Organization for Scientific Research (NWO) for financially supporting this research.

    FundersFunder number
    Netherlands Organization for Scientific Research
    Seventh Framework Programme210999
    European Research Council
    Nederlandse Organisatie voor Wetenschappelijk Onderzoek
    Foundation for Fundamental Research on Matter

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