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Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies
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Number of Authors: 13
2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 40, 14236-14246 p.Article in journal (Refereed) Published
Abstract [en]

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-alpha-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 alpha-synuclein (alpha-syn) aggregation to toxic oligomers by an, off-pathway mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-beta component region of alpha-syn, which are responsible for alpha-syn's membrane intercalation and self-assembly, thus changing the overall conformation of alpha-syn. CP-2 also remodels alpha-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular alpha-syn in neuronal cells overexpressing alpha-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.

Place, publisher, year, edition, pages
2016. Vol. 22, no 40, 14236-14246 p.
Keyword [en]
amyloids, inhibitors, cyclic D, L-alpha-peptides, synucleinophathies, alpha-synuclein
National Category
Chemical Sciences
URN: urn:nbn:se:su:diva-135028DOI: 10.1002/chem.201601830ISI: 000384698200005PubMedID: 27539220OAI: diva2:1045276
Available from: 2016-11-08 Created: 2016-10-31 Last updated: 2016-11-08Bibliographically approved

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Wallin, CeciliaWärmländer, Sebastian K. T. S.Gräslund, Astrid
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Department of Biochemistry and Biophysics
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