An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

Emil Dandanell Agerschou; Patrick Flagmeier; Theodora Saridaki; Céline Galvagnion; Daniel Komnig; Laetitia Heid; Vibha Prasad; Hamed Shaykhalishahi; Dieter Willbold; Christopher M Dobson; Aaron Voigt; Björn Falkenbürger; Wolfgang Hoyer; Alexander K Buell

doi:10.7554/eLife.46112

An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

Emil Dandanell Agerschou, Patrick Flagmeier, Theodora Saridaki, Céline Galvagnion, Daniel Komnig, Laetitia Heid, Vibha Prasad, Hamed Shaykhalishahi, Dieter Willbold, Christopher M Dobson, Aaron Voigt, Björn Falkenbürger, Wolfgang Hoyer, Alexander K Buell

22 Citationer (Scopus)

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 formation of visible α-synuclein aggregates. In flies, AS69 reduced a-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 substoichiometric inhibition of nucleation processes.

Originalsprog	Engelsk
Tidsskrift	eLife
Vol/bind	8
ISSN	2050-084X
DOI	https://doi.org/10.7554/eLife.46112 https://doi.org/10.7554/eLife.46112
Status	Udgivet - aug. 2019
Udgivet eksternt	Ja

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10.7554/eLife.46112
10.7554/eLife.46112Licens: CC BY

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Agerschou, E. D., Flagmeier, P., Saridaki, T., Galvagnion, C., Komnig, D., Heid, L., Prasad, V., Shaykhalishahi, H., Willbold, D., Dobson, C. M., Voigt, A., Falkenbürger, B., Hoyer, W., & Buell, A. K. (2019). An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils. eLife, 8. https://doi.org/10.7554/eLife.46112, https://doi.org/10.7554/eLife.46112

Agerschou, ED, Flagmeier, P, Saridaki, T, Galvagnion, C, Komnig, D, Heid, L, Prasad, V, Shaykhalishahi, H, Willbold, D, Dobson, CM, Voigt, A, Falkenbürger, B, Hoyer, W & Buell, AK 2019, 'An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils', eLife, bind 8. https://doi.org/10.7554/eLife.46112, https://doi.org/10.7554/eLife.46112

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title = "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{\textquoteright}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 formation of visible α-synuclein aggregates. In flies, AS69 reduced a-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 substoichiometric inhibition of nucleation processes.",

author = "Agerschou, {Emil Dandanell} and Patrick Flagmeier and Theodora Saridaki and C{\'e}line Galvagnion and Daniel Komnig and Laetitia Heid and Vibha Prasad and Hamed Shaykhalishahi and Dieter Willbold and Dobson, {Christopher M} and Aaron Voigt and Bj{\"o}rn Falkenb{\"u}rger and Wolfgang Hoyer and Buell, {Alexander K}",

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year = "2019",

month = aug,

doi = "10.7554/eLife.46112",

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T1 - An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

AU - Agerschou, Emil Dandanell

AU - Flagmeier, Patrick

AU - Saridaki, Theodora

AU - Galvagnion, Céline

AU - Komnig, Daniel

AU - Heid, Laetitia

AU - Prasad, Vibha

AU - Shaykhalishahi, Hamed

AU - Willbold, Dieter

AU - Dobson, Christopher M

AU - Voigt, Aaron

AU - Falkenbürger, Björn

AU - Hoyer, Wolfgang

AU - Buell, Alexander K

PY - 2019/8

Y1 - 2019/8

N2 - 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 formation of visible α-synuclein aggregates. In flies, AS69 reduced a-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 substoichiometric inhibition of nucleation processes.

AB - 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 formation of visible α-synuclein aggregates. In flies, AS69 reduced a-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 substoichiometric inhibition of nucleation processes.

U2 - 10.7554/eLife.46112

DO - 10.7554/eLife.46112

M3 - Journal article

C2 - 31389332

SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

ER -

An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

Abstract

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