The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations

Plaques of the amyloid beta (Aß) peptide are a pathological hallmark of Alzheimer's disease (AD), the most common form of dementia. Mutations in Aß also cause familial forms of AD (fAD). Here, we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggrega...

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Detalhes bibliográficos
Autores: Seuma, Mireia, Faure, Andre J., Badia, Marta, Lehner, Ben, 1978-, Bolognesi, Benedetta
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/46821
Acesso em linha:http://hdl.handle.net/10230/46821
http://dx.doi.org/10.7554/eLife.63364
Access Level:acceso abierto
Palavra-chave:Alzheimer, Malaltia d&apos
-- Aspectes genètics
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spelling The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutationsSeuma, MireiaFaure, Andre J.Badia, MartaLehner, Ben, 1978-Bolognesi, BenedettaAlzheimer, Malaltia d&apos-- Aspectes genèticsPlaques of the amyloid beta (Aß) peptide are a pathological hallmark of Alzheimer's disease (AD), the most common form of dementia. Mutations in Aß also cause familial forms of AD (fAD). Here, we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the empirical nucleation scores accurately identify all known dominant fAD mutations in Aß, genetically validating that the mechanism of nucleation in a cell-based assay is likely to be very similar to the mechanism that causes the human disease. These results provide the first comprehensive atlas of how mutations alter the formation of any amyloid fibril and a resource for the interpretation of genetic variation in Aß.Work in the lab of BB is supported by the Spanish Ministry of Science, Innovation and Universities through the project RTI2018-101491-A-I00 (MICIU/FEDER), by the CERCA Program/Generalitat de Catalunya and by funding from the Agencia de Gestio d’Ajuts Universitaris i de Recerca (2019FI_B 01311) to MS Work in the lab of BL is supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Science, Innovation and Universities (BFU2017-89488-P and SEV-2012–0208), the Bettencourt Schueller Foundation, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322.), and the CERCA Program/Generalitat de Catalunyae-Life Sciences Publications202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/46821http://dx.doi.org/10.7554/eLife.63364reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésElife. 2021 Feb 1;10:e63364info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-Pinfo:eu-repo/grantAgreement/EC/H2020/616434© 2021, Seuma et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are creditedhttps://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/468212026-06-12T07:21:37Z
dc.title.none.fl_str_mv The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
title The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
spellingShingle The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
Seuma, Mireia
Alzheimer, Malaltia d&apos
-- Aspectes genètics
title_short The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
title_full The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
title_fullStr The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
title_full_unstemmed The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
title_sort The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
dc.creator.none.fl_str_mv Seuma, Mireia
Faure, Andre J.
Badia, Marta
Lehner, Ben, 1978-
Bolognesi, Benedetta
author Seuma, Mireia
author_facet Seuma, Mireia
Faure, Andre J.
Badia, Marta
Lehner, Ben, 1978-
Bolognesi, Benedetta
author_role author
author2 Faure, Andre J.
Badia, Marta
Lehner, Ben, 1978-
Bolognesi, Benedetta
author2_role author
author
author
author
dc.subject.none.fl_str_mv Alzheimer, Malaltia d&apos
-- Aspectes genètics
topic Alzheimer, Malaltia d&apos
-- Aspectes genètics
description Plaques of the amyloid beta (Aß) peptide are a pathological hallmark of Alzheimer's disease (AD), the most common form of dementia. Mutations in Aß also cause familial forms of AD (fAD). Here, we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the empirical nucleation scores accurately identify all known dominant fAD mutations in Aß, genetically validating that the mechanism of nucleation in a cell-based assay is likely to be very similar to the mechanism that causes the human disease. These results provide the first comprehensive atlas of how mutations alter the formation of any amyloid fibril and a resource for the interpretation of genetic variation in Aß.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/46821
http://dx.doi.org/10.7554/eLife.63364
url http://hdl.handle.net/10230/46821
http://dx.doi.org/10.7554/eLife.63364
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Elife. 2021 Feb 1;10:e63364
info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
info:eu-repo/grantAgreement/EC/H2020/616434
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv e-Life Sciences Publications
publisher.none.fl_str_mv e-Life Sciences Publications
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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