The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer’s disease mutations
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Spain
- Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
- Universitat Pompeu Fabra (UPF), Spain
- ICREA, Pg. Lluís Companys, Spain
Figures
Figure 1 with 1 supplement
Deep mutagenesis of amyloid beta (Aß) nucleation.
(A) In vivo Aß selection assay. Aß fused to the Sup35N domain seeds aggregation of endogenous Sup35p causing a read-through of a premature UGA in the Ade1-14 reporter, allowing the cells to grow in …
Figure 1—figure supplement 1
Reproducibility of the assay and correlation with in vitro fibril nucleation.
(A) Percentage of yeast growth in medium lacking adenine for sup35N, amyloid beta (Aß) and sup35N-Aß constructions. (B) Correlation of nucleation scores for biological replicates 1 and 3 (n = 4,124 …
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Figure 1—figure supplement 1—source data 1
Raw colony counts from independent testing of the strains expressing the variants reported in Figure 1—figure supplement 1A.
- https://cdn.elifesciences.org/articles/63364/elife-63364-fig1-figsupp1-data1-v2.xlsx
Figure 2 with 1 supplement
Modular organization of mutational effects in amyloid beta (Aß).
(A and B) Nucleation scores distribution for single (A) and double (B) amino acid (aa) mutants. n = 468 (missense), n = 31 (nonsense), n = 90 (synonymous) for singles, and n = 14,015 (missense) for …
Figure 2—figure supplement 1
Mutational effects in amyloid beta (Aß).
(A) Heatmap of nucleation score categories for single amino acid (aa) variants at different false discovery rates (FDR) (blue: increased nucleation, orange: decreased nucleation, grey: not different …
Figure 3 with 2 supplements
Determinants of amyloid beta (Aß) nucleation.
(A) Effect of single aa mutants on nucleation for each Aß position. The wild-type (WT) aa and position are indicated on the x-axis and coloured on the basis of aa type. The horizontal line indicates …
Figure 3—figure supplement 1
Determinants of amyloid beta (Aß) nucleation.
(A and B) Nucleation scores as a function of aggregation predictors (Tango, Waltz, Zyggregator, and Camsol; Tartaglia and Vendruscolo, 2008; Fernandez-Escamilla et al., 2004; Oliveberg, 2010; Sormann…
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Figure 3—figure supplement 1—source data 1
Raw colony counts from indepednet testing of the strains expressing the N-terminal truncated varaints reported in Figure 3—figure supplement 1C.
- https://cdn.elifesciences.org/articles/63364/elife-63364-fig3-figsupp1-data1-v2.xlsx
Figure 3—figure supplement 2
Effect of mutations to each specific amino acid (aa) on amyloid beta (Aß) nucleation.
Mutations to other aa are indicated in grey. The wild-type (WT) AA is indicated with ‘*’. The horizontal line indicates WT nucleation score (0). Point size indicates false discovery rate (FDR) (big, …
Figure 4 with 1 supplement
Amyloid beta (Aß) nucleation accurately discriminates dominant familial Alzheimer’s disease (fAD) variants.
Receiver operating characteristic (ROC) curves for 12 fAD mutants versus all other single aa mutants in the dataset. Area under the curve (AUC) values are indicated in the legend. Diagonal dashed …
Figure 4—figure supplement 1
Discrimination of familial Alzheimer’s disease (fAD) variants by aggregation and variant effect predictors.
(A and B) Receiver operating characteristic (ROC) curves built using 12 fAD mutants versus all other single amino acid (aa) mutants in the dataset for variant effect predictors (A) and aggregation …
Figure 5 with 2 supplements
Mutational landscape of the amyloid beta (Aß) amyloid fibril.
Average effect of mutations visualized on the cross-section of an Aß amyloid fibril (PDB accession 5KK3; Colvin et al., 2016). Nucleation gatekeeper residues and known familial Alzheimer’s disease (f…
Figure 5—figure supplement 1
Modular organization of Aß42 and Aß40 polymorphs.
Linear organization of the Aß42 and Aß40 fibrils. Disordered/unstructured and structured residues are indicated.
Figure 5—figure supplement 2
Modular organization of mutational effects and gatekeepers visualized on Aß42 polymorphs.
Average effect of mutations visualized on the cross-section of various amyloid beta (Aß) amyloid polymorphs: PDB accession 2BEG (Lührs et al., 2005), 2MXU (Xiao et al., 2015), 5AEF (Schmidt et al., …
Additional files
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Supplementary file 1
Table listing the impact on aggregation rates for 16 Aß42 variants for which these measurements could be retrieved from the literature.
For the same variants, the table also reports nucleation scores, as quantified in this study, and the qualitative agreement or disagreement with the previously published data.
- https://cdn.elifesciences.org/articles/63364/elife-63364-supp1-v2.xlsx
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Supplementary file 2
Table listing the mutations in Aß42 that significantly increase nucleation score and that are therefore proposed as novel familial Alzheimer’s disease (fAD) candidates.
For each mutation, the corresponding nucleation score (NS) is reported.
- https://cdn.elifesciences.org/articles/63364/elife-63364-supp2-v2.xlsx
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Supplementary file 3
List of oligonucleotides used in this study.
- https://cdn.elifesciences.org/articles/63364/elife-63364-supp3-v2.xlsx
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Supplementary file 4
Processed data required to make all analyses and figures in this paper.
Read counts, nucleation scores, and associated error terms are reported for each Aß42 variant in each replicate. See sheet one for a deeper explanation of headers.
- https://cdn.elifesciences.org/articles/63364/elife-63364-supp4-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/63364/elife-63364-transrepform-v2.docx
