title: α-Synuclein aggregation, seeding and inhibition by scyllo-inositol.
abstract: Recent literature demonstrates the accelerated aggregation of α-synuclein, a protein implicated in the pathogenesis of Parkinson's disease (PD), by the presence of preformed fibrillar conformers in vitro. Furthermore, these preformed fibrillar seeds are suggested to accelerate pathological induction in vivo when injected into the brains of mice. Variation in the results of in vivo studies is proposed to be caused by α-synuclein conformational variants. To investigate the impact of amino acid sequence on seeding efficiency, human and mouse α-synuclein seeds, which vary at 7 amino acid residues, were generated and cross-seeding kinetics studied. Using transmission electron microscopy (TEM), we confirmed that mouse α-synuclein aggregated more rapidly than human α-synuclein. Subsequently, we determined that seeding of human and mouse α-synuclein was more rapid in the presence of seeds generated from the same species. In addition, an established amyloid inhibitor, scyllo-inositol, was examined for potential inhibitory effects on α-synuclein aggregation. TEM analysis of protein:inhibitor assays demonstrated that scyllo-inositol inhibits the aggregation of α-synuclein, suggesting the therapeutic potential of the small molecule in PD.
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M4N 3M5, ON, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Ibrahim
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M4N 3M5, ON, Canada. Electronic address: jmclaurin@sri.utoronto.ca.
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
mesh_terms: D000818:Animals; D001665:Binding Sites; D007294:Inositol / Q000737:chemistry*; D051379:Mice; D046912:Multiprotein Complexes / Q000138:chemical synthesis*; D011485:Protein Binding; D013045:Species Specificity; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D046912:Multiprotein Complexes; D051844:alpha-Synuclein; C009217:scyllitol; D007294:Inositol
keywords: Parkinson's disease; Protein misfolding; Seeding; scyllo-Inositol; α-Synuclein