Cryo-EM structure of alpha-synuclein fibrils

  1. Ricardo Guerrero-Ferreira
  2. Nicholas M I Taylor
  3. Daniel Mona
  4. Philippe Ringler
  5. Matthias E Lauer
  6. Roland Riek
  7. Markus Britschgi
  8. Henning Stahlberg  Is a corresponding author
  1. University of Basel, Switzerland
  2. Roche Innovation Center Basel, Switzerland
  3. ETH Zürich, Switzerland

Abstract

Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy structure at a resolution of 3.4Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

Data availability

The cryo-EM image data are available in the Electron Microscopy Public Image Archive, entry number EMPIAR-10195. The 3D map is available in the EMDB, entry number EMD-4276. The atomic coordinates are available at the PDB, entry number PDB 6FLT.

The following data sets were generated
    1. Guerrero-Ferreira R
    2. Taylor NMI
    3. Mona D
    4. Riek R
    5. Britschgi M
    6. Stahlberg H
    (2018) Structure of alpha-synuclein fibrils
    Publicly available at the Electron Microscopy Data Bank (accession no. EMD-4276).
    1. Guerrero-Ferreira R
    2. Taylor NMI
    3. Mona D
    4. Riek R
    5. Britschgi M
    6. Stahlberg H
    (2018) Structure of alpha-synuclein fibrils
    Publicly available at the Electron Microscopy Public Image Archive (accession no. EMPIAR-10195).

Article and author information

Author details

  1. Ricardo Guerrero-Ferreira

    Center for Cellular Imaging and NanoAnalytics (C-CINA), University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3664-8277
  2. Nicholas M I Taylor

    Center for Cellular Imaging and NanoAnalytics (C-CINA), University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0761-4921
  3. Daniel Mona

    Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area/Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    Daniel Mona, Employed by Hoffmann-La Roche. There are no other competing interests to declare..
  4. Philippe Ringler

    Center for Cellular Imaging and NanoAnalytics (C-CINA), University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
  5. Matthias E Lauer

    Roche Pharma Research and Early Development, Chemical Biology, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    Matthias E Lauer, Employed by Hoffmann-La Roche. There are no other competing interests to declare..
  6. Roland Riek

    Laboratory of Physical Chemistry, ETH Zürich, Zürich, Switzerland
    Competing interests
    No competing interests declared.
  7. Markus Britschgi

    Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area/Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    Markus Britschgi, Employed by Hoffmann-La Roche. There are no other competing interests to declare..
  8. Henning Stahlberg

    Center for Cellular Imaging and NanoAnalytics (C-CINA), University of Basel, Basel, Switzerland
    For correspondence
    Henning.Stahlberg@unibas.ch
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1185-4592

Funding

Swiss National Science Foundation (CRSII3_154461 and CRSII5_177195)

  • Ricardo Guerrero-Ferreira
  • Nicholas M I Taylor

Synapsis Foundation Switzerland

  • Henning Stahlberg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sjors HW Scheres, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: March 5, 2018
  2. Accepted: July 1, 2018
  3. Accepted Manuscript published: July 3, 2018 (version 1)
  4. Version of Record published: August 14, 2018 (version 2)

Copyright

© 2018, Guerrero-Ferreira et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ricardo Guerrero-Ferreira
  2. Nicholas M I Taylor
  3. Daniel Mona
  4. Philippe Ringler
  5. Matthias E Lauer
  6. Roland Riek
  7. Markus Britschgi
  8. Henning Stahlberg
(2018)
Cryo-EM structure of alpha-synuclein fibrils
eLife 7:e36402.
https://doi.org/10.7554/eLife.36402
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    Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.

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