Journal
PLOS BIOLOGY
Volume 5, Issue 11, Pages 2493-2500Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.0050290
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Funding
- Medical Research Council [G0500306] Funding Source: researchfish
- MRC [G0500306] Funding Source: UKRI
- Medical Research Council [G0500306] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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 A beta(42) peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of A beta(42) 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 A beta 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.
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