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

  1. Mireia Seuma
  2. Andre Faure
  3. Marta Badia
  4. Ben Lehner  Is a corresponding author
  5. Benedetta Bolognesi  Is a corresponding author
  1. IBEC, Spain
  2. 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

The following data sets were generated

Article and author information

Author details

  1. Mireia Seuma

    IBEC, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Andre Faure

    Systems Biology, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4471-5994
  3. Marta Badia

    IBEC, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Ben Lehner

    Systems Biology, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
    For correspondence
    ben.lehner@crg.eu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8817-1124
  5. Benedetta Bolognesi

    IBEC, Barcelona, Spain
    For correspondence
    bbolognesi@ibecbarcelona.eu
    Competing interests
    The authors declare that no competing interests exist.

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.

Reviewing Editor

  1. Patrik Verstreken, KU Leuven, Belgium

Version history

  1. Received: September 23, 2020
  2. Accepted: February 1, 2021
  3. Accepted Manuscript published: February 1, 2021 (version 1)
  4. Version of Record published: March 9, 2021 (version 2)

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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  1. Mireia Seuma
  2. Andre Faure
  3. Marta Badia
  4. Ben Lehner
  5. Benedetta Bolognesi
(2021)
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

Share this article

https://doi.org/10.7554/eLife.63364

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