Journal Article

FZJ-2019-02989

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

2019
eLife Sciences Publications Cambridge

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Please use a persistent id in citations: http://hdl.handle.net/2128/23866  doi:10.7554/eLife.46112

Abstract: 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 occurrence of α-synuclein oligomers and of visible α-synuclein aggregates. In flies, AS69 reduced α-synuclein aggregates and the locomotor deficit resulting from α-synuclein expression in neuronal cells. In a mouse model based on the intracerebral injection of pre-formed α-synuclein seed fibrills (PFFs), AS69 co-injection reduced the density of dystrophic neurites observed three months later. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited auto-catalytic 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. These results represent a new paradigm that high affinity monomer binders can be strongly sub-stoichiometric inhibitors of nucleation processes.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2019

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