Journal Article

DZNE-2020-07261

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils.

Agerschou, E. D. ; Flagmeier, P. ; Saridaki, T. ; Galvagnion, C.DZNE* ; Komnig, D. ; Heid, L. ; Prasad, V. ; Shaykhalishahi, H. ; Willbold, D. ; Dobson, C. M. ; Voigt, A. ; Falkenburger, B. ; Hoyer, W. ; Buell, A. K. (Corresponding author)

2019
eLife Sciences Publications Cambridge

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Please use a persistent id in citations: doi:10.7554/eLife.46112

Abstract: 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.

Keyword(s): Amyloid: antagonists & inhibitors (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Protein Aggregation, Pathological (MeSH) ; Protein Multimerization: drug effects (MeSH) ; Recombinant Proteins: genetics (MeSH) ; Recombinant Proteins: metabolism (MeSH) ; alpha-Synuclein: metabolism (MeSH)

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Contributing Institute(s):

1. Neurodegeneration and Neuroprotection in Parkinson´s Disease (AG Di Monte)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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