An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
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.
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.
Metrics
-
- 5,406
- views
-
- 839
- downloads
-
- 54
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
During delayed ballistic reaches, motor areas consistently display movement-specific activity patterns prior to movement onset. It is unclear why these patterns arise: while they have been proposed to seed an initial neural state from which the movement unfolds, recent experiments have uncovered the presence and necessity of ongoing inputs during movement, which may lessen the need for careful initialization. Here, we modeled the motor cortex as an input-driven dynamical system, and we asked what the optimal way to control this system to perform fast delayed reaches is. We find that delay-period inputs consistently arise in an optimally controlled model of M1. By studying a variety of network architectures, we could dissect and predict the situations in which it is beneficial for a network to prepare. Finally, we show that optimal input-driven control of neural dynamics gives rise to multiple phases of preparation during reach sequences, providing a novel explanation for experimentally observed features of monkey M1 activity in double reaching.
-
- Neuroscience
Humans make irrational decisions in the presence of irrelevant distractor options. There is little consensus on whether decision making is facilitated or impaired by the presence of a highly rewarding distractor, or whether the distractor effect operates at the level of options’ component attributes rather than at the level of their overall value. To reconcile different claims, we argue that it is important to consider the diversity of people’s styles of decision making and whether choice attributes are combined in an additive or multiplicative way. Employing a multi-laboratory dataset investigating the same experimental paradigm, we demonstrated that people used a mix of both approaches and the extent to which approach was used varied across individuals. Critically, we identified that this variability was correlated with the distractor effect during decision making. Individuals who tended to use a multiplicative approach to compute value, showed a positive distractor effect. In contrast, a negative distractor effect (divisive normalisation) was prominent in individuals tending towards an additive approach. Findings suggest that the distractor effect is related to how value is constructed, which in turn may be influenced by task and subject specificities. This concurs with recent behavioural and neuroscience findings that multiple distractor effects co-exist.