Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity : In Vitro and Mechanistic Studies

• 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.

Ämnesord

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Nyckelord

amyloids

inhibitors

cyclic D

L-alpha-peptides

synucleinophathies

alpha-synuclein

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)