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000140939 0247_ $$2doi$$a10.7554/eLife.46112
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000140939 1001_ $$0P:(DE-HGF)0$$aAgerschou, Emil Dandanell$$b0
000140939 245__ $$aAn engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils.
000140939 260__ $$aCambridge$$beLife Sciences Publications$$c2019
000140939 264_1 $$2Crossref$$3online$$beLife Sciences Publications, Ltd$$c2019-08-21
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000140939 520__ $$aRemoving 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.
000140939 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000140939 650_2 $$2MeSH$$aAmyloid: antagonists & inhibitors
000140939 650_2 $$2MeSH$$aHEK293 Cells
000140939 650_2 $$2MeSH$$aHumans
000140939 650_2 $$2MeSH$$aProtein Aggregation, Pathological
000140939 650_2 $$2MeSH$$aProtein Multimerization: drug effects
000140939 650_2 $$2MeSH$$aRecombinant Proteins: genetics
000140939 650_2 $$2MeSH$$aRecombinant Proteins: metabolism
000140939 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000140939 7001_ $$0P:(DE-HGF)0$$aFlagmeier, Patrick$$b1
000140939 7001_ $$0P:(DE-HGF)0$$aSaridaki, Theodora$$b2
000140939 7001_ $$0P:(DE-2719)2811987$$aGalvagnion, Céline$$b3$$udzne
000140939 7001_ $$0P:(DE-HGF)0$$aKomnig, Daniel$$b4
000140939 7001_ $$0P:(DE-HGF)0$$aHeid, Laetitia$$b5
000140939 7001_ $$0P:(DE-HGF)0$$aPrasad, Vibha$$b6
000140939 7001_ $$0P:(DE-HGF)0$$aShaykhalishahi, Hamed$$b7
000140939 7001_ $$0P:(DE-HGF)0$$aWillbold, Dieter$$b8
000140939 7001_ $$0P:(DE-HGF)0$$aDobson, Christopher M$$b9
000140939 7001_ $$0P:(DE-HGF)0$$aVoigt, Aaron$$b10
000140939 7001_ $$0P:(DE-HGF)0$$aFalkenburger, Bjoern$$b11
000140939 7001_ $$0P:(DE-HGF)0$$aHoyer, Wolfgang$$b12
000140939 7001_ $$0P:(DE-HGF)0$$aBuell, Alexander K$$b13$$eCorresponding author
000140939 77318 $$2Crossref$$3journal-article$$a10.7554/elife.46112$$b : eLife Sciences Publications, Ltd, 2019-08-21$$teLife$$v8$$x2050-084X$$y2019
000140939 773__ $$0PERI:(DE-600)2687154-3$$a10.7554/eLife.46112$$gVol. 8, p. e46112$$pe46112$$q8<e46112$$teLife$$v8$$x2050-084X$$y2019
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000140939 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721797
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