An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils

eLife

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[1] Department of Chemistry, University of Cambridge, Cambridge, United Kingdom;Centre for Misfolding Diseases, University of Cambridge, Cambridge, United Kingdom;Department of Neurology, RWTH Aachen University, Aachen, Germany;Department of Neurology, RWTH Aachen University, Aachen, Germany;Department of Neurology, Dresden University Medical Center, Dresden, Germany;Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany;Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany;Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark;Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany;Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany;RG Mechanisms of Neuroprotection, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Pharmacology and Drug Design, University of Copenhagen, Copenhagen, Denmark;

关键词: amyloid;    inhibtion;    nucleation;    β-wrapin;    AS69;    Parkinson's disease;    D. melanogaster;   

DOI  :  10.7554/eLife.46112

来源: publisher

【 摘 要 】

10.7554/eLife.46112.001Removing 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 self-interaction of α-synuclein and formation 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 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-α-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.

【 授权许可】

CC BY