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

Research output: Contribution to journalJournal articlepeer-review

  • Emil Dandanell Agerschou
  • Patrick Flagmeier
  • Theodora Saridaki
  • Galvagnion-Büll, Céline
  • Daniel Komnig
  • Laetitia Heid
  • Vibha Prasad
  • Hamed Shaykhalishahi
  • Dieter Willbold
  • Christopher M Dobson
  • Aaron Voigt
  • Björn Falkenbürger
  • Wolfgang Hoyer
  • Alexander K Buell

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.

Original languageEnglish
JournaleLife
Volume8
ISSN2050-084X
DOIs
Publication statusE-pub ahead of print - 7 Aug 2019
Externally publishedYes

Bibliographical note

© 2019, Agerschou et al.

ID: 225521743