%0 Journal Article
%A Agerschou, Emil Dandanell
%A Flagmeier, Patrick
%A Saridaki, Theodora
%A Galvagnion, Céline
%A Komnig, Daniel
%A Heid, Laetitia
%A Prasad, Vibha
%A Shaykhalishahi, Hamed
%A Willbold, Dieter
%A Dobson, Christopher M
%A Voigt, Aaron
%A Falkenburger, Bjoern
%A Hoyer, Wolfgang
%A Buell, Alexander K
%T An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils.
%J eLife
%V 8
%@ 2050-084X
%C Cambridge
%I eLife Sciences Publications
%M DZNE-2020-07261
%P e46112
%D 2019
%X Removing or preventing the formation of [Formula: see text]-synuclein aggregates is a plausible strategy against Parkinson's disease. To this end, we have engineered the [Formula: see text]-wrapin AS69 to bind monomeric [Formula: see text]-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of [Formula: see text]-synuclein and formation of visible [Formula: see text]-synuclein aggregates. In flies, AS69 reduced [Formula: see text]-synuclein aggregates and the locomotor deficit resulting from [Formula: see text]-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-[Formula: see text]-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.
%K Amyloid: antagonists & inhibitors
%K HEK293 Cells
%K Humans
%K Protein Aggregation, Pathological
%K Protein Multimerization: drug effects
%K Recombinant Proteins: genetics
%K Recombinant Proteins: metabolism
%K alpha-Synuclein: metabolism
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:31389332
%2 pmc:PMC6721797
%R 10.7554/eLife.46112
%U https://pub.dzne.de/record/140939