Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
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.
Luheshi
Leila M
LM
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Tartaglia
Gian Gaetano
GG
Brorsson
Ann-Christin
AC
Pawar
Amol P
AP
Watson
Ian E
IE
Chiti
Fabrizio
F
Vendruscolo
Michele
M
Lomas
David A
DA
Dobson
Christopher M
CM
Crowther
Damian C
DC
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D008124:Locomotion / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)