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, Bjoern Falkenburger, Wolfgang Hoyer, Alexander K. Buell*

*Corresponding author for this work

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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-wrap in AS69 to bind monomeric α-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of a synuclein and 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.

Original languageEnglish
Article numbere46112
JournaleLife
Volume8
Number of pages31
ISSN2050-084X
DOIs
Publication statusPublished - 2019

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