Structural insights into amyloid oligomers of the Parkinson disease related protein a-synuclein.

GALLEA JI; CELEJ MS

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2014 vol. 289 p. 26733 - 26742

0021-9258

The presence of intraneuronal deposits mainly formed by amyloid fibrils of the presynaptic protein a-synuclein (AS) is a hallmark of Parkinson disease. Currently, neurotoxicity is attributed to prefibrillar oligomeric species rather than the insoluble aggregates, though their mechanisms of toxicity remain elusive. Structural details of the supramolecular organization of AS oligomers are critically needed in order 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 b-sheet core in the fibrillar state, although their spatial arrangement may differ in the two aggregated forms. On the other hand, 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.