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An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils.
Agerschou, Emil Dandanell; Flagmeier, Patrick; Saridaki, Theodora; Galvagnion, Céline; Komnig, Daniel; Heid, Laetitia; Prasad, Vibha; Shaykhalishahi, Hamed; Willbold, Dieter; Dobson, Christopher M; Voigt, Aaron; Falkenburger, Bjoern; Hoyer, Wolfgang; Buell, Alexander K.
Afiliación
  • Agerschou ED; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Flagmeier P; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
  • Saridaki T; Centre for Misfolding Diseases, University of Cambridge, Cambridge, United Kingdom.
  • Galvagnion C; Department of Neurology, RWTH Aachen University, Aachen, Germany.
  • Komnig D; RG Mechanisms of Neuroprotection, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • Heid L; Department of Pharmacology and Drug Design, University of Copenhagen, Copenhagen, Denmark.
  • Prasad V; Department of Neurology, RWTH Aachen University, Aachen, Germany.
  • Shaykhalishahi H; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Willbold D; Department of Neurology, RWTH Aachen University, Aachen, Germany.
  • Dobson CM; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Voigt A; Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Falkenburger B; Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany.
  • Hoyer W; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
  • Buell AK; Centre for Misfolding Diseases, University of Cambridge, Cambridge, United Kingdom.
Elife ; 82019 08 21.
Article en En | MEDLINE | ID: mdl-31389332
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Recombinantes / Alfa-Sinucleína / Amiloide Límite: Humans Idioma: En Revista: Elife Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Recombinantes / Alfa-Sinucleína / Amiloide Límite: Humans Idioma: En Revista: Elife Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido