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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.

Author information

1
Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
2
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
3
Department of Neurology, RWTH Aachen University, Aachen, Germany.
4
Biotechnology and Biomedicine, Technical University of Denmark, Kgs Lyngby, Denmark.

Abstract

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.

KEYWORDS:

D. melanogaster; molecular biophysics; neuroscience; structural biology

PMID:
31389332
DOI:
10.7554/eLife.46112
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