TY  - JOUR
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  - Falkenburger, Bjoern
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  - DZNE-2020-07261
SP  - e46112
PY  - 2019
AB  - 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.
KW  - Amyloid: antagonists & inhibitors
KW  - HEK293 Cells
KW  - Humans
KW  - Protein Aggregation, Pathological
KW  - Protein Multimerization: drug effects
KW  - Recombinant Proteins: genetics
KW  - Recombinant Proteins: metabolism
KW  - alpha-Synuclein: metabolism
LB  - PUB:(DE-HGF)16
C6  - pmid:31389332
C2  - pmc:PMC6721797
DO  - DOI:10.7554/eLife.46112
UR  - https://pub.dzne.de/record/140939
ER  -