title: Inhibition of alpha-synuclein fibril assembly by small molecules: analysis using epitope-specific antibodies.
abstract: The conversion of soluble peptides and proteins into amyloid fibrils and/or intermediate oligomers is believed to be the central event in the pathogenesis of most human neurodegenerative diseases. Existing treatments are at best symptomatic. Accordingly, small molecule inhibitors of amyloid fibril formation and their mechanisms are of great interest. Here we report that the conformational changes undergone by alpha -synuclein as it assembles into amyloid fibrils can be detected by epitope-specific antibodies. We show that the conformations of polyphenol-bound alpha-synuclein monomers and dimers differ from those of unbound monomers and resemble amyloid fibrils. This strongly suggests that small molecule inhibitors bind and stabilize intermediates of amyloid fibril formation, consistent with the view that inhibitor-bound molecular species are on-pathway intermediates.
authors.affiliation: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Oikawa
authors.forename: Motokuni
authors.initials: M
authors.lastname: Yonetani
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hisanaga
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000906:Antibodies / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019149:Bioreactors; D019281:Dimerization; D000939:Epitopes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D011485:Protein Binding; D011487:Protein Conformation; D013696:Temperature; D013997:Time Factors; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D000682:Amyloid; D000906:Antibodies; D000939:Epitopes; D051844:alpha-Synuclein