An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation

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• dc.contributor.author Seuma, Mireia
• dc.contributor.author Lehner, Ben, 1978-
• dc.contributor.author Bolognesi, Benedetta
• dc.date.accessioned 2023-01-24T07:19:42Z
• dc.date.available 2023-01-24T07:19:42Z
• dc.date.issued 2022
• dc.description.abstract Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type-amino acid (AA) substitutions-despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer's disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.
• dc.description.sponsorship M.S. was supported by a fellowship from Agencia de Gestio d’Ajuts Universitaris i de Recerca (2019FI_B 01311). Work in the lab of BB and BL is supported by the la Caixa Research Foundation project ‘DeepAmyloids’ (LCF/PR/HR21/52410004). Work in the lab of BB is also supported by the Spanish Ministry of Science, Innovation and Universities (PID2021-127761OB-I00 and RYC2020-028861-I, funded by MCIN/AEI/ 10.13039/501100011033, “ERDF A way of making Europe” and “ESF Investing in your future”) and the CERCA Program/Generalitat de Catalunya. Work in the lab of BL is also supported by a European Research Council (ERC) Advanced Grant (‘Mutanomics’ 883742), the Spanish Ministry of Science, Innovation and Universities (PID2020-118723GB-I00), the Bettencourt Schueller Foundation, the AXA Research Foundation, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322) and the CERCA Program/Generalitat de Catalunya. We also acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership and the Centro de Excelencia Severo Ochoa. We thank the Chernoff lab for providing strains and plasmids and the CRG Genomics core technology for sequencing. We also thank Andre Faure and Marta Badia for advice on data analysis, Leire Moriones for assistance with validation experiments and Xavier Salvatella and Carla Garcia for discussing our data.
• dc.format.mimetype application/pdf
• dc.identifier.citation Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. DOI: 10.1038/s41467-022-34742-3
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-34742-3
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/55411
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2022 Nov 18;13(1):7084
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-127761OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RYC2020-028861-I
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-118723GB-I00
• dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Biophysics
• dc.subject.keyword Computational biology and bioinformatics
• dc.subject.keyword Medical genomics
• dc.subject.keyword Systems biology
• dc.title An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion