%0 Journal Article
%A Agerschou, Emil D.
%A Saridaki, Theodora
%A Flagmeier, Patrick
%A Galvagnion, Céline
%A Komnig, Daniel
%A Nagpal, Akansha
%A Gasterich, Natalie
%A Heid, Laetitia
%A Prasad, Vibha
%A Shaykhalishahi, Hamed
%A Voigt, Aaron
%A Willbold, Dieter
%A Dobson, Christopher M.
%A Falkenburger, Björn H.
%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 FZJ-2019-02989
%P e46112
%D 2019
%X 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 occurrence of α-synuclein oligomers and 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 a mouse model based on the intracerebral injection of pre-formed α-synuclein seed fibrills (PFFs), AS69 co-injection reduced the density of dystrophic neurites observed three months later. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited auto-catalytic 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. These results represent a new paradigm that high affinity monomer binders can be strongly sub-stoichiometric inhibitors of nucleation processes.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:31389332
%U <Go to ISI:>//WOS:000484182000001
%R 10.7554/eLife.46112
%U https://juser.fz-juelich.de/record/862747