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

Luheshi, LM; Tartaglia, GG; Brorsson, AC; Pawar, AP; Watson, IE; Chiti, F; Vendruscolo, M; ... Crowther, DC; + view all (2007) Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity. PLoS Biology , 5 (11) , Article e290. 10.1371/journal.pbio.0050290. Green open access

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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.

Type: Article
Title: Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
Location: US
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pbio.0050290
Publisher version: http://dx.doi.org/10.1371/journal.pbio.0050290
Language: English
Additional information: © 2007 Luheshi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC2043051
Keywords: Alzheimer Disease, Amyloid beta-Peptides, Animals, Disease Models, Animal, Drosophila melanogaster, Locomotion, Longevity, Mutation, Missense, Peptide Fragments
UCL classification: UCL
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/1385910
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