1. Neuroscience
  2. Structural Biology and Molecular Biophysics
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An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

  1. Emil Dandanell Agerschou
  2. Patrick Flagmeier
  3. Theodora Saridaki
  4. Céline Galvagnion
  5. Daniel Komnig
  6. Laetitia Heid
  7. Vibha Prasad
  8. Hamed Shaykhalishahi
  9. Dieter Willbold
  10. Christopher M Dobson
  11. Aaron Voigt
  12. Björn Falkenburger  Is a corresponding author
  13. Wolfgang Hoyer  Is a corresponding author
  14. Alexander K Buell  Is a corresponding author
  1. Heinrich Heine University Düsseldorf, Germany
  2. University of Cambridge, United Kingdom
  3. RWTH Aachen University, Germany
  4. Technical University of Denmark, Denmark
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Cite this article as: eLife 2019;8:e46112 doi: 10.7554/eLife.46112

Abstract

Removing or preventing the formation of α-synuclein aggregates is a plausible strategy against Parkinson's disease. To this end we have engineered the β-wrapin AS69 to bind monomeric α-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of α-synuclein and the formation of visible α-synuclein aggregates. In flies, AS69 reduced α-synuclein aggregates and the locomotor deficit resulting from α-synuclein expression in neuronal cells. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited both primary and autocatalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69-α-synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition of secondary nucleation. These results represent a new paradigm that high affinity monomer binders can lead to strongly sub-stoichiometric inhibition of nucleation processes.

Article and author information

Author details

  1. Emil Dandanell Agerschou

    Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Patrick Flagmeier

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1204-5340
  3. Theodora Saridaki

    Department of Neurology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Céline Galvagnion

    Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Daniel Komnig

    Department of Neurology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6312-5236
  6. Laetitia Heid

    Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Vibha Prasad

    Department of Neurology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Hamed Shaykhalishahi

    Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Dieter Willbold

    Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0065-7366
  10. Christopher M Dobson

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Aaron Voigt

    Department of Neurology, RWTH Aachen University, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0428-7462
  12. Björn Falkenburger

    Department of Neurology, RWTH Aachen University, Aachen, Germany
    For correspondence
    bfalkenburger@ukaachen.de
    Competing interests
    The authors declare that no competing interests exist.
  13. Wolfgang Hoyer

    Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
    For correspondence
    wolfgang.hoyer@hhu.de
    Competing interests
    The authors declare that no competing interests exist.
  14. Alexander K Buell

    Biotechnology and Biomedicine, Technical University of Denmark, Kgs Lyngby, Denmark
    For correspondence
    alebu@dtu.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1161-3622

Funding

Leverhulme Trust

  • Alexander K Buell

Boehringer Ingelheim Fonds

  • Patrick Flagmeier

Studienstiftung des Deutschen Volkes

  • Patrick Flagmeier

Alexander von Humboldt-Stiftung

  • Céline Galvagnion

Parkinson's and Movement Disorder Foundation

  • Alexander K Buell

H2020 European Research Council (MCSA grant agreement No 706551)

  • Céline Galvagnion

Novo Nordisk Foundation

  • Alexander K Buell

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

Reviewing Editor

  1. Andrew B West, Duke University, United States

Publication history

  1. Received: February 25, 2019
  2. Accepted: August 4, 2019
  3. Accepted Manuscript published: August 7, 2019 (version 1)
  4. Accepted Manuscript updated: August 21, 2019 (version 2)

Copyright

© 2019, Agerschou 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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