Self-Assembled Cyclic d,l-α-Peptides as Generic Conformational Inhibitors of the α-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Marina Chemerovski-Glikman, Eva Rozentur-Shkop, Michal Richman, Asaf Grupi, Asaf Getler, Haim Y. Cohen, Hadassa Shaked, Cecilia Wallin, Sebastian K.T.S. Wärmländer, Elisha Haas, Astrid Gräslund, Jordan H. Chill, Shai Rahimipour

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic d,l-α-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson′s disease associated α-synuclein (α-syn) aggregation to toxic oligomers by an „off-pathway“ mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-β component region of α-syn, which are responsible for α-syn′s membrane intercalation and self-assembly, thus changing the overall conformation of α-syn. CP-2 also remodels α-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α-syn in neuronal cells overexpressing α-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.

Original languageEnglish
Pages (from-to)14236-14246
Number of pages11
JournalChemistry - A European Journal
Volume22
Issue number40
DOIs
StatePublished - 26 Sep 2016
Externally publishedYes

Keywords

  • amyloids
  • cyclic d,l-α-peptides
  • inhibitors
  • synucleinophathies
  • α-synuclein

ASJC Scopus subject areas

  • General Chemistry
  • Catalysis
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Self-Assembled Cyclic d,l-α-Peptides as Generic Conformational Inhibitors of the α-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies'. Together they form a unique fingerprint.

Cite this