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 aggregati...

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Autores principales:	Leila M Luheshi, Gian Gaetano Tartaglia, Ann-Christin Brorsson, Amol P Pawar, Ian E Watson, Fabrizio Chiti, Michele Vendruscolo, David A Lomas, Christopher M Dobson, Damian C Crowther
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c4e1adf9f10c4b98853de2fa4e79ca68
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spelling	oai:doaj.org-article:c4e1adf9f10c4b98853de2fa4e79ca682021-11-25T05:33:05ZSystematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.1544-91731545-788510.1371/journal.pbio.0050290https://doaj.org/article/c4e1adf9f10c4b98853de2fa4e79ca682007-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.0050290https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Protein 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.Leila M LuheshiGian Gaetano TartagliaAnn-Christin BrorssonAmol P PawarIan E WatsonFabrizio ChitiMichele VendruscoloDavid A LomasChristopher M DobsonDamian C CrowtherPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 5, Iss 11, p e290 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Leila M Luheshi Gian Gaetano Tartaglia Ann-Christin Brorsson Amol P Pawar Ian E Watson Fabrizio Chiti Michele Vendruscolo David A Lomas Christopher M Dobson Damian C Crowther Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
description	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.
format	article
author	Leila M Luheshi Gian Gaetano Tartaglia Ann-Christin Brorsson Amol P Pawar Ian E Watson Fabrizio Chiti Michele Vendruscolo David A Lomas Christopher M Dobson Damian C Crowther
author_facet	Leila M Luheshi Gian Gaetano Tartaglia Ann-Christin Brorsson Amol P Pawar Ian E Watson Fabrizio Chiti Michele Vendruscolo David A Lomas Christopher M Dobson Damian C Crowther
author_sort	Leila M Luheshi
title	Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
title_short	Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
title_full	Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
title_fullStr	Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
title_full_unstemmed	Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.
title_sort	systematic in vivo analysis of the intrinsic determinants of amyloid beta pathogenicity.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/c4e1adf9f10c4b98853de2fa4e79ca68
work_keys_str_mv	AT leilamluheshi systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT giangaetanotartaglia systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT annchristinbrorsson systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT amolppawar systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT ianewatson systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT fabriziochiti systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT michelevendruscolo systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT davidalomas systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT christophermdobson systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity AT damianccrowther systematicinvivoanalysisoftheintrinsicdeterminantsofamyloidbetapathogenicity
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Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.

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