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

Mitra Pirhaghi, Signe Andrea Frank, Parvez Alam, Janni Nielsen, Vita Sereikaite, Arpit Gupta, Kristian Strømgaard, Maria Andreasen, Deepak Sharma, Ali Akbar Saboury*, Daniel Erik Otzen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review


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, 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 cytotoxicity and permeabilization of large anionic unilamellar vesicles. 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 (Kdapp 2.7 and 31.2 μM, respectively). p216 reduced αSOs-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 αSOs cytotoxicity by about 20%. We conclude that p216 is a promising starting point from which to develop peptides targeting toxic αSOs in Parkinson's disease.

Original languageEnglish
Article number102688
JournalJournal of Biological Chemistry
Publication statusPublished - Dec 2022


  • amyloid fibrillation
  • cell penetrating peptides
  • lipid vesicles
  • oligomer
  • Parkinson's disease
  • peptide array
  • peptide inhibitors
  • α-synuclein


Dive into the research topics of 'A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers'. Together they form a unique fingerprint.

Cite this