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