title: Inhibiting α-synuclein oligomerization by stable cell-penetrating β-synuclein fragments recovers phenotype of Parkinson's disease model flies.
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 identified 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.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shaltiel-Karyo
authors.forename: Moran
authors.initials: M
authors.lastname: Frenkel-Pinter
authors.forename: Nirit
authors.initials: N
authors.lastname: Egoz-Matia
authors.forename: Anat
authors.initials: A
authors.lastname: Frydman-Marom
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051846:beta-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D051844:alpha-Synuclein; D051846:beta-Synuclein