TY  - JOUR
AU  - Agerschou, Emil D.
AU  - Saridaki, Theodora
AU  - Flagmeier, Patrick
AU  - Galvagnion, Céline
AU  - Komnig, Daniel
AU  - Nagpal, Akansha
AU  - Gasterich, Natalie
AU  - Heid, Laetitia
AU  - Prasad, Vibha
AU  - Shaykhalishahi, Hamed
AU  - Voigt, Aaron
AU  - Willbold, Dieter
AU  - Dobson, Christopher M.
AU  - Falkenburger, Björn H.
AU  - Hoyer, Wolfgang
AU  - Buell, Alexander K.
TI  - An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
JO  - eLife
VL  - 8
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - FZJ-2019-02989
SP  - e46112
PY  - 2019
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 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31389332
UR  - <Go to ISI:>//WOS:000484182000001
DO  - DOI:10.7554/eLife.46112
UR  - https://juser.fz-juelich.de/record/862747
ER  -