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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.
FlyBase ID
FBrf0243396
Publication Type
Research paper
Abstract

Removing or preventing the formation of <up>Formula: see text</up>-synuclein aggregates is a plausible strategy against Parkinson's disease. To this end, we have engineered the <up>Formula: see text</up>-wrapin AS69 to bind monomeric <up>Formula: see text</up>-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of <up>Formula: see text</up>-synuclein and formation of visible <up>Formula: see text</up>-synuclein aggregates. In flies, AS69 reduced <up>Formula: see text</up>-synuclein aggregates and the locomotor deficit resulting from <up>Formula: see text</up>-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-<up>Formula: see text</up>-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.

PubMed ID
PubMed Central ID
PMC6721797 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    eLife
    Title
    eLife
    ISBN/ISSN
    2050-084X
    Data From Reference
    Alleles (7)
    Genes (4)
    Human Disease Models (1)
    Natural transposons (1)
    Insertions (1)
    Experimental Tools (1)
    Transgenic Constructs (7)