title: Monitoring and targeting the initial dimerization stage of amyloid self-assembly.
abstract: Amyloid deposits are pathological hallmark of a large group of human degenerative disorders of unrelated etiologies. While accumulating evidence suggests that early oligomers may account for tissue degeneration, most detection tools do not allow the monitoring of early association events. Here we exploit bimolecular fluorescence complementation analysis to detect and quantify the dimerization of three major amyloidogenic polypeptides; islet amyloid polypeptide, β-amyloid and α-synuclein. The constructed systems provided direct visualization of protein-protein interactions in which only assembled dimers display strong fluorescent signal. Potential inhibitors that interfere with the initial intermolecular interactions of islet amyloid polypeptide were further identified using this system. Moreover, the identified compounds were able to inhibit the aggregation and cytotoxicity of islet amyloid polypeptide, demonstrating the importance of targeting amyloid dimer formation for future drug development.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv 69978 (Israel).
authors.forename: Yaron
authors.initials: Y
authors.lastname: Bram
authors.forename: Ayala
authors.initials: A
authors.lastname: Lampel
authors.forename: Ronit
authors.initials: R
authors.lastname: Shaltiel-Karyo
authors.forename: Anat
authors.initials: A
authors.lastname: Ezer
authors.forename: Roni
authors.initials: R
authors.lastname: Scherzer-Attali
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000648:ultrastructure; D055808:Drug Discovery; D005453:Fluorescence; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000648:ultrastructure; D008958:Models, Molecular; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000473:pathology; D055503:Protein Multimerization / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates; D051844:alpha-Synuclein
keywords: amyloid inhibitors; amyloid self-assembly; complementation assays; fluorescence; self-assembly