An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

TY - JOUR

T1 - An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

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 - Falkenbürger, Björn

AU - Hoyer, Wolfgang

AU - Buell, Alexander K

N1 - © 2019, Agerschou et al.

PY - 2019/8

Y1 - 2019/8

N2 - 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 self-interaction of α-synuclein and formation of visible α-synuclein aggregates. In flies, AS69 reduced a-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 substoichiometric inhibition of nucleation processes.

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 self-interaction of α-synuclein and formation of visible α-synuclein aggregates. In flies, AS69 reduced a-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 substoichiometric inhibition of nucleation processes.

U2 - 10.7554/eLife.46112

DO - 10.7554/eLife.46112

M3 - Journal article

C2 - 31389332

SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

ER -