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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2007
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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) |
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Biology (General) QH301-705.5 |
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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 |
| _version_ |
1718414664641019904 |