An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
- Heinrich Heine University Düsseldorf, Germany
- University of Cambridge, United Kingdom
- RWTH Aachen University, Germany
- Technical University of Denmark, Denmark
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.
Data availability
- Numerical data represented in the graphs for cell culture and fly experiments will be made publicly available on osf.io as we did for previous publications.- The numerical data for the biophysical experiments will be made publicly available within the same repository on osf.io.- The raw images of the gels used in the publication will be made publicly available.All data have been deposited on osf.io ( https://osf.io/6n2gs/?view_only=7eb7024d8ecb460a817cd0ed35978339 ) and will be made available in the event of publication
Article and author information
Author details
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
- Andrew B West, Duke University, United States
Version history
- Received: February 25, 2019
- Accepted: August 4, 2019
- Accepted Manuscript published: August 7, 2019 (version 1)
- Accepted Manuscript updated: August 21, 2019 (version 2)
- Version of Record published: September 3, 2019 (version 3)
- Version of Record updated: December 11, 2019 (version 4)
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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An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
eLife 8:e46112.
https://doi.org/10.7554/eLife.46112
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