Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.

TitleSystematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
Publication TypeJournal Article
Year of Publication2007
AuthorsLuheshi LM, Tartaglia GG, Brorsson AC, Pawar AP, Watson IE, Chiti F, Vendruscolo M, Lomas DA, Dobson CM, Crowther DC
JournalPLoS Biol.
Volume5
Paginatione290
Date PublishedOct
Abstract

Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Abeta42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Abeta42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Abeta and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism.

URLhttp://dx.doi.org/10.1371/journal.pbio.0050290
DOI10.1371/journal.pbio.0050290