Self‐Assembled Cyclic d, l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies. Issue 40 (19th August 2016)

• Record Type: Journal Article
• Authors: Chemerovski‐Glikman, Marina; Rozentur‐Shkop, Eva; Richman, Michal; Grupi, Asaf; Getler, Asaf; Cohen, Haim Y.; Shaked, Hadassa; Wallin, Cecilia; Wärmländer, Sebastian K. T. S.; Haas, Elisha; Gräslund, Astrid; Chill, Jordan H.; Rahimipour, Shai
• Is Part Of: Chemistry. Volume 22:Issue 40(2016)
• Page Start: 14236
• Page End: 14246
• Publication Date: 2016-08-19
• Subjects: amyloids -- inhibitors -- cyclic d, l-α-peptides -- synucleinophathies -- α-synuclein; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201601830
• Languages: English
• ISSNs: 0947-6539

Abstract

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, cyclicd, l ‐α‐peptideCP‐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 thatCP‐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. Abstract : Parkinson′s disease treatment : Self‐assembled cyclicd, l ‐α‐peptides with similar structural and functional properties to those of amyloids act as generic conformational inhibitors of the Parkinson′s disease associated protein α‐synuclein to inhibit its aggregation to toxic oligomers. The cyclic peptides also remodel α‐synuclein fibrils to nontoxic species and permeate α‐synuclein overexpressing cells to reduce the accumulation and toxicity of intracellular α‐synuclein.