title: Self-Assembled Cyclic d,l-α-Peptides as Generic Conformational Inhibitors of the α-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies.
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.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Chemerovski-Glikman
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Eva
authors.initials: E
authors.lastname: Rozentur-Shkop
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Richman
authors.affiliation: Department of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Grupi
authors.affiliation: Department of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Getler
authors.affiliation: Department of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Haim Y
authors.initials: HY
authors.lastname: Cohen
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Hadassa
authors.initials: H
authors.lastname: Shaked
authors.affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, 10691, Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wallin
authors.affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, 10691, Stockholm, Sweden.
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
authors.affiliation: Department of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Elisha
authors.initials: E
authors.lastname: Haas
authors.affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, 10691, Stockholm, Sweden.
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
authors.forename: Jordan H
authors.initials: JH
authors.lastname: Chill
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel. rahimis@biu.ac.il.
authors.forename: Shai
authors.initials: S
authors.lastname: Rahimipour
mesh_terms: D000682:Amyloid / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D010456:Peptides, Cyclic; D066329:Protein Aggregates; D051844:alpha-Synuclein
keywords: amyloids; cyclic d,l-α-peptides; inhibitors; synucleinophathies; α-synuclein