Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy

  1. Ricardo Guerrero-Ferreira
  2. Nicholas MI Taylor
  3. Ana-Andreea Arteni
  4. Pratibha Kumari
  5. Daniel Mona
  6. Philippe Ringler
  7. Markus Britschgi
  8. Matthias E Lauer
  9. Ali Makky
  10. Joeri Verasdonck
  11. Roland Riek
  12. Ronald Melki
  13. Beat H Meier
  14. Anja Böckmann
  15. Luc Bousset
  16. Henning Stahlberg  Is a corresponding author
  1. University of Basel, Switzerland
  2. University of Copenhagen, Denmark
  3. CNRS, Université Paris Sud, Université Paris-Saclay, France
  4. ETH Zürich, Switzerland
  5. Roche Innovation Center Basel, Switzerland
  6. CNRS, France
  7. University of Lyon, France

Abstract

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.

Data availability

Raw cryo-EM micrographs are available in EMPIAR, entry numbers EMPIAR-10323. The 3D maps are available in the EMDB, entry numbers EMD-10307 (α-Syn polymorph 2a) and EMD-10305 (α-Syn-polymorph 2b). Atomic coordinates are available at the PDB with entry numbers PDB 6SSX (α-Syn polymorph 2a) and PDB 6SST (α-Syn polymorph 2b).

The following data sets were generated

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 MI Taylor

    Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0761-4921
  3. Ana-Andreea Arteni

    Institut de Biologie Intégrative de la Cellule, CNRS, Université Paris Sud, Université Paris-Saclay, Paris, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6462-905X
  4. Pratibha Kumari

    Laboratory of Physical Chemistry, ETH Zürich, Zürich, Switzerland
    Competing interests
    No competing interests declared.
  5. 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, employee at Roche and may additionally hold Roche stock/stock options.
  6. Philippe Ringler

    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:" 0000-0003-4346-5089
  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, employee at Roche and may additionally hold Roche stock/stock options.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6151-4257
  8. Matthias E Lauer

    Roche Pharma Research and Early Development, Chemical Biology, Roche Innovation Center Basel, Basel, Switzerland
    Competing interests
    Matthias E Lauer, employee at Roche and may additionally hold Roche stock/stock options.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3252-8718
  9. Ali Makky

    Institut Galien Paris-Sud, CNRS, Université Paris Sud, Université Paris-Saclay, Paris, France
    Competing interests
    No competing interests declared.
  10. Joeri Verasdonck

    Laboratory of Physical Chemistry, ETH Zürich, Zürich, Switzerland
    Competing interests
    No competing interests declared.
  11. Roland Riek

    Laboratory of Physical Chemistry, ETH Zürich, Zürich, Switzerland
    Competing interests
    No competing interests declared.
  12. Ronald Melki

    Institut Fancois Jacob (MIRCen), CNRS, Paris, France
    Competing interests
    No competing interests declared.
  13. Beat H Meier

    Laboratory of Physical Chemistry, ETH Zürich, Zürich, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9107-4464
  14. Anja Böckmann

    Molecular Microbiology and Structural Biochemistry, University of Lyon, Lyon, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8149-7941
  15. Luc Bousset

    Institut Fancois Jacob (MIRCen), CNRS, Paris, France
    Competing interests
    No competing interests declared.
  16. Henning Stahlberg

    Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, 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

Novo Nordisk (NNF14CC0001)

  • Nicholas MI Taylor

SERI (17.00038)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

Fondation Bettencourt Schueller

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

fondation pour la Recherche Medicale (Contract DEQ 20160334896)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

Fondation Simone et Cino Del Duca of the Institut de France and

  • Beat H Meier
  • Luc Bousset

EC Joint Program on Neurodegenerative Diseases (TransPathND)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

FRISBI (ANR-10-INSB-05-01)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

EC Joint Program on Neurodegenerative Diseases (ANR-17-JPCD-0005-01)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

EC Joint Program on Neurodegenerative Diseases (ANR-17-JPCD-0002-02)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

EC Joint Program on Neurodegenerative Diseases (Protest-70)

  • Ana-Andreea Arteni
  • Beat H Meier
  • Luc Bousset

Synapsis Foundation (n/a)

  • Ricardo Guerrero-Ferreira
  • Henning Stahlberg

Heidi-Seiler Stiftung (n/a)

  • Ricardo Guerrero-Ferreira
  • Henning Stahlberg

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII3_154461)

  • Ricardo Guerrero-Ferreira
  • Nicholas MI Taylor
  • Henning Stahlberg

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII5_177195)

  • Ricardo Guerrero-Ferreira
  • Henning Stahlberg

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (20020_178792)

  • Ricardo Guerrero-Ferreira
  • Henning Stahlberg

Agence Nationale de la Recherche (ANR-12-BS08-0013-01)

  • Ronald Melki
  • Luc Bousset

LABEX ECOFECT (ANR-11-LABX-0048)

  • Anja Böckmann

H2020 (IMPRiND)

  • Ana-Andreea Arteni
  • Ronald Melki
  • Luc Bousset

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

Version history

  1. Received: May 30, 2019
  2. Accepted: November 30, 2019
  3. Accepted Manuscript published: December 9, 2019 (version 1)
  4. Version of Record published: January 13, 2020 (version 2)

Copyright

© 2019, 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 MI Taylor
  3. Ana-Andreea Arteni
  4. Pratibha Kumari
  5. Daniel Mona
  6. Philippe Ringler
  7. Markus Britschgi
  8. Matthias E Lauer
  9. Ali Makky
  10. Joeri Verasdonck
  11. Roland Riek
  12. Ronald Melki
  13. Beat H Meier
  14. Anja Böckmann
  15. Luc Bousset
  16. Henning Stahlberg
(2019)
Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
eLife 8:e48907.
https://doi.org/10.7554/eLife.48907

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https://doi.org/10.7554/eLife.48907

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