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A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers: A penetratin-derived peptide against α-synuclein oligomers.

ABSTRACT: Parkinson's Disease (PD) is a neurodegenerative movement disorder associated with the intracellular aggregation of α-synuclein (α-syn). Cytotoxicity is mainly associated with the oligomeric species (αSOs) formed at early stages in α-syn aggregation. Consequently, there is an intense focus on the discovery of novel inhibitors such as peptides to inhibit oligomer formation and toxicity. Here, using peptide arrays, we identified nine peptides with high specificity and affinity for αSOs. Of these, peptides p194, p235, and p249 diverted α-syn aggregation from fibrils to amorphous aggregates with reduced β-structures and increased random coil content. However, they did not reduce αSO's cytotoxicity and permeabilization of large anionic unilamellar vesicles (LUV). In parallel, we identified a non-self-aggregating peptide (p216), derived from the cell-penetrating peptide penetratin, which showed 12-fold higher binding affinity to αSOs than to α-syn monomers (K_d^app 2.7 and 31.2 μM, respectively). p216 reduced αSOs-induced LUV membrane permeability at 10^-1-10^-3 mg/ml by almost 100%, was not toxic to SH-SY5Y cells, and reduced αSOs cytotoxicity by about 20%. We conclude that p216 is a promising starting point from which to develop peptides targeting toxic αSOs in PD.

SUBMITTER: Pirhaghi M

PROVIDER: S-EPMC9791135 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers.

Pirhaghi Mitra M Frank Signe Andrea SA Alam Parvez P Nielsen Janni J Sereikaite Vita V Gupta Arpit A Strømgaard Kristian K Andreasen Maria M Sharma Deepak D Saboury Ali Akbar AA Otzen Daniel Erik DE

The Journal of biological chemistry 20221110 12

Parkinson's disease is a neurodegenerative movement disorder associated with the intracellular aggregation of α-synuclein (α-syn). Cytotoxicity is mainly associated with the oligomeric species (αSOs) formed at early stages in α-syn aggregation. Consequently, there is an intense focus on the discovery of novel inhibitors such as peptides to inhibit oligomer formation and toxicity. Here, using peptide arrays, we identified nine peptides with high specificity and affinity for αSOs. Of these, peptid ...[more]

PMID: 36370848

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Project description:BackgroundProtein membrane transduction domains that are able to cross the plasma membrane are present in several transcription factors, such as the homeodomain proteins and the viral proteins such as Tat of HIV-1. Their discovery resulted in both new concepts on the cell communication during development, and the conception of cell penetrating peptide vectors for internalisation of active molecules into cells. A promising cell penetrating peptide is Penetratin, which crosses the cell membranes by a receptor and metabolic energy-independent mechanism. Recent works have claimed that Penetratin and similar peptides are internalized by endocytosis, but other endocytosis-independent mechanisms have been proposed. Endosomes or plasma membranes crossing mechanisms are not well understood. Previously, we have shown that basic peptides induce membrane invaginations suggesting a new mechanism for uptake, "physical endocytosis".Methodology/principal findingsHerein, we investigate the role of membrane lipid phases on Penetratin induced membrane deformations (liquid ordered such as in "raft" microdomains versus disordered fluid "non-raft" domains) in membrane models. Experimental data show that zwitterionic lipid headgroups take part in the interaction with Penetratin suggesting that the external leaflet lipids of cells plasma membrane are competent for peptide interaction in the absence of net negative charges. NMR and X-ray diffraction data show that the membrane perturbations (tubulation and vesiculation) are associated with an increase in membrane negative curvature. These effects on curvature were observed in the liquid disordered but not in the liquid ordered (raft-like) membrane domains.Conclusions/significanceThe better understanding of the internalisation mechanisms of protein transduction domains will help both the understanding of the mechanisms of cell communication and the development of potential therapeutic molecular vectors. Here we showed that the membrane targets for these molecules are preferentially the fluid membrane domains and that the mechanism involves the induction of membrane negative curvature. Consequences on cellular uptake are discussed.

Dataset Information

A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers: A penetratin-derived peptide against α-synuclein oligomers.

Publications

A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers.

Similar Datasets

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