title: Structural insights into amyloid oligomers of the Parkinson disease-related protein α-synuclein.
abstract: The presence of intraneuronal deposits mainly formed by amyloid fibrils of the presynaptic protein α-synuclein (AS) is a hallmark of Parkinson disease. Currently, neurotoxicity is attributed to prefibrillar oligomeric species rather than the insoluble aggregates, although their mechanisms of toxicity remain elusive. Structural details of the supramolecular organization of AS oligomers are critically needed to decipher the structure-toxicity relationship underlying their pathogenicity. In this study, we employed site-specific fluorescence to get a deeper insight into the internal architecture of AS oligomeric intermediates. We demonstrate that AS oligomers are ordered assemblies possessing a well defined pattern of intermolecular contacts. Some of these contacts involve regions that form the β-sheet core in the fibrillar state, although their spatial arrangement may differ in the two aggregated forms. However, even though the two termini are excluded from the fibrillar core, they are engaged in a number of intermolecular interactions within the oligomer. Therefore, substantial structural remodeling of early oligomeric interactions is essential for fibril growth. The intermolecular contacts identified in AS oligomers can serve as targets for the rational design of anti-amyloid compounds directed at preventing oligomeric interactions/reorganizations.
authors.affiliation: Departamento de Química Biológica, Centro de Investigaciones en Química Biológica de Córdoba (Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Gallea
authors.affiliation: Departamento de Química Biológica, Centro de Investigaciones en Química Biológica de Córdoba (Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina. Electronic address: mcelej@mail.fcq.unc.edu.ar.
authors.forename: M Soledad
authors.initials: MS
authors.lastname: Celej
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010300:Parkinson Disease; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein
keywords: Alpha-synuclein (a-Synuclein); Amyloid; Fluorescence; Parkinson Disease; Protein Aggregation