Artículos de revistas
Structural Insights into Amyloid Oligomers of the Parkinson Disease-related Protein α-Synuclein
Fecha
2014-09Registro en:
Gallea, Jose Ignacio; Celej, Maria Soledad; Structural Insights into Amyloid Oligomers of the Parkinson Disease-related Protein α-Synuclein; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 289; 39; 9-2014; 26733-26742
0021-9258
CONICET Digital
CONICET
Autor
Gallea, Jose Ignacio
Celej, Maria Soledad
Resumen
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.