Agerschou, E.D., Flagmeier, P., Saridaki, T., Galvagnion, C., Komnig, D., Heid, L., Prasad, V., Shaykhalishahi, H., Willbold, D., Dobson, C.M., Voigt, A., Falkenburger, B., Hoyer, W., Buell, A.K. (2019). An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils.  eLife 8(): e46112.

FBrf0243396

Research paper

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.

PMC6721797 (PMC) (EuropePMC)