Inhibiting α-synuclein oligomerization by stable cell-penetrating β-synuclein fragments recovers phenotype of parkinson's disease model flies

Ronit Shaltiel-Karyo, Moran Frenkel-Pinter, Nirit Egoz-Matia, Anat Frydman-Marom, Deborah E. Shalev, Daniel Segal, Ehud Gazit

Research output: Contribution to journalArticlepeer-review

Abstract

The intracellular oligomerization of α-synuclein is associated with Parkinson's disease and appears to be an important target for disease-modifying treatment. Yet, to date, there is no specific inhibitor for this aggregation process. Using unbiased systematic peptide array analysis, we indentified molecular interaction domains within the β-synuclein polypeptide that specifically binds α-synuclein. Adding such peptide fragments to α-synuclein significantly reduced both amyloid fibrils and soluble oligomer formation in vitro. A retro-inverso analogue of the best peptide inhibitor was designed to develop the identified molecular recognition module into a drug candidate. While this peptide shows indistinguishable activity as compared to the native peptide, it is stable in mouse serum and penetrates α-synuclein over-expressing cells. The interaction interface between the D-amino acid peptide and α-synuclein was mapped by Nuclear Magnetic Resonance spectroscopy. Finally, administering the retro-inverso peptide to a Drosophila model expressing mutant A53T α-synuclein in the nervous system, resulted in a significant recovery of the behavioral abnormalities of the treated flies and in a significant reduction in α-synuclein accumulation in the brains of the flies. The engineered retro-inverso peptide can serve as a lead for developing a novel class of therapeutic agents to treat Parkinson's disease.

Original languageEnglish
Article numbere13863
JournalPLoS ONE
Volume5
Issue number11
DOIs
StatePublished - 2010

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