The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
- IBEC, Spain
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Spain
Abstract
Plaques of the amyloid beta (Aβ) peptide are a pathological hallmark of Alzheimer's Disease (AD), the most common form of dementia. Mutations in Aβ 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 Aβ. 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 AB42, 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 Aβ.
Data availability
Raw sequencing data and the processed data table (Supplementary file 3) have been deposited in NCBI's Gene Expression Omnibus (GEO) as record GSE151147. All code used for data analysis is available at https://github.com/BEBlab
Article and author information
Author details
Funding
Ministerio de Ciencia, Innovación y Universidades (RTI2018-101491-A-I00)
- Benedetta Bolognesi
Ministerio de Ciencia, Innovación y Universidades (BFU2017-89488-P)
- Ben Lehner
H2020 European Research Council (616434)
- Ben Lehner
AGAUR (SGR 1322)
- Ben Lehner
Agència de Gestió d'Ajuts Universitaris i de Recerca (2019FI_B 01311)
- Mireia Seuma
Fondation Bettencourt Schueller (Prize)
- Ben Lehner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Seuma et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer's disease mutations
eLife 10:e63364.
https://doi.org/10.7554/eLife.63364
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