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Elife. 2019 Aug 7;8. pii: e46112. doi: 10.7554/eLife.46112. [Epub ahead of print]

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

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Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Department of Neurology, RWTH Aachen University, Aachen, Germany.
Biotechnology and Biomedicine, Technical University of Denmark, Kgs Lyngby, Denmark.


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 self-interaction of α-synuclein and the 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.


D. melanogaster; molecular biophysics; neuroscience; structural biology

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