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

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• dc.contributor.author Seuma, Mireia
• dc.contributor.author Faure, Andre J.
• dc.contributor.author Badia, Marta
• dc.contributor.author Lehner, Ben, 1978-
• dc.contributor.author Bolognesi, Benedetta
• dc.date.accessioned 2021-03-17T09:56:32Z
• dc.date.available 2021-03-17T09:56:32Z
• dc.date.issued 2021
• dc.description.abstract 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.
• dc.description.sponsorship 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 Catalunya
• dc.format.mimetype application/pdf
• dc.identifier.citation Seuma M, Faure AJ, Badia M, Lehner B, Bolognesi B. The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations. Elife. 2021 Feb 1;10:e63364. DOI: 10.7554/eLife.63364
• dc.identifier.doi http://dx.doi.org/10.7554/eLife.63364
• dc.identifier.issn 2050-084X
• dc.identifier.uri http://hdl.handle.net/10230/46821
• dc.language.iso eng
• dc.publisher e-Life Sciences Publications
• dc.relation.ispartof Elife. 2021 Feb 1;10:e63364
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/616434
• dc.rights © 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 credited
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.other Alzheimer, Malaltia d' -- Aspectes genètics
• dc.title The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion