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

Parkinson???s disease is a neurodegenerative movement disorder associated with the intracellular aggregation of ??-synuclein (??-syn). Cytotoxicity is mainly associated with the oligomeric species (??SOs) formed at early stages in ??-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 ??SOs. Of these, peptides p194, p235, and p249 diverted ??-syn aggregation from fibrils to amorphous aggregates with reduced II-structures and increased random coil content. However, they did not reduce ??SO cytotoxicity and permeabilization of large anionic unilamellar vesicles. In parallel, we identified a non??? self-aggregating peptide (p216), derived from the cellpenetrating peptide penetratin, which showed 12-fold higher binding affinity to ??SOs than to ??-syn monomers (Kdapp 2.7 and 31.2 ??M, respectively). p216 reduced ??SOs-induced large anionic unilamellar vesicle membrane permeability at 10???1 to 10???3 mg/ml by almost 100%, was not toxic to SH-SY5Y cells, and reduced ??SOs cytotoxicity by about 20%. We conclude that p216 is a promising starting point from which to develop peptides targeting toxic ??SOs in Parkinson???s disease.