Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

Humphrey, Jack; Venkatesh, Sanan; Hasan, Rahat; Herb, Jake T.; Lopes, Kátia de Paiva; Küçükali, Fahri; Byrska-Bishop, Marta; Evani, Uday Shankar; Narzisi, Giuseppe; Fagegaltier, Delphine; Sleegers, Kristel; Phatnani, Hemali; Knowles, David A.; Fratta, Pietro; Raj, Towfique

doi:10.1101/2021.08.31.21262682

Cited by 6 publications

(9 citation statements)

References 139 publications

(168 reference statements)

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“…11a). CHIT1, GPNMB and LYZ were the most strongly upregulated genes in ALS spinal cord, consistent with a recent report 5 . Functional enrichment analysis revealed that upregulated genes were enriched in the stress response, programmed cell death and the DNA damage response, whilst downregulated genes were enriched in neuronal functions (Extended Data Fig.…”

Section: Als Postmortem Tissue Shows P53 Activationsupporting

confidence: 92%

“…To identify whether iPSN ALS gene expression signatures are also found in postmortem tissue, we compared our findings with postmortem spinal cord RNA-seq from the NYGC ALS cohort, consisting of tissue from 153 ALS patients and 80 controls 5,31 . We found 14,529 differentially expressed genes in postmortem ALS versus control spinal cord samples, with 6,417 upregulated and 8,112 downregulated in ALS (FDR < 0.05; Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Postmortem spinal cord ALS RNA-seq samples were derived from samples from the New York Genome Centre (NYGC) ALS consortium. Samples from non-spinal cord sites were excluded as well as samples that failed quality control as described previously 5 . Processed gene counts are available from Zenodo accession 6385747 .…”

Section: Methodsmentioning

confidence: 99%

“…A major hurdle in identifying the causes of ALS has been the inaccessibility to patient motor neurons. Whilst postmortem ALS tissue has revealed important insights, it represents the end-stage of the disease with only few surviving motor neurons [5][6][7][8] . Human-induced pluripotent stem cell (iPSC)-derived motor neurons (iPSNs) offer a potential solution.…”

Section: Introductionmentioning

confidence: 99%

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Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability

Ziff

Neeves

Mitchell

et al. 2022

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is characterised by progressive motor neuron degeneration but there is marked genetic and clinical heterogeneity1. Identifying common mechanisms of ALS amongst this diversity has been challenging, however, a systematic framework examining motor neurons across the ALS spectrum may reveal unifying insights. Here, we present the most comprehensive compendium of ALS human-induced pluripotent stem cell-derived motor neurons (iPSNs) from 429 donors across 15 datasets including Answer ALS and NeuroLINCS, spanning 10 ALS mutations and sporadic ALS. Using gold-standard reproducible bioinformatic workflows, we identify that ALS iPSNs show common activation of the DNA damage response and p53 signalling, which was replicated in the NYGC ALS postmortem cohort of 203 spinal cord samples. The strongest p53 activation was observed in C9orf72 repeat expansions but was also independently increased in TARDBP, FUS and sporadic subgroups. ALS iPSNs showed extensive splicing alterations and enrichment of SNVs, indels and gene fusions, which may contribute to their damage-induced mutation signature. Our results integrate the global landscape of motor neuron alterations in ALS, revealing that genome instability is a common hallmark of ALS motor neurons and provides a resource to identify future ALS drug targets.

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Section: Als Postmortem Tissue Shows P53 Activationsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability

Ziff

Neeves

Mitchell

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…To identify whether iPSN ALS gene expression signatures are also found in postmortem tissue, we compared our findings with postmortem spinal cord RNAseq from the NYGC ALS cohort, consisting of tissue from 153 ALS patients and 80 controls 5,31 . We found 14,529 differentially expressed genes in postmortem ALS versus control spinal cord samples, with 6,417 upregulated and 8,112 downregulated in ALS (FDR < 0.05; Extended Data Fig.…”

Section: Als Postmortem Tissue Shows P53 Activationmentioning

confidence: 99%

Genome instability underlies an augmented DNA damage response in familial and sporadic ALS human iPSC-derived motor neurons

Ziff

Neeves

Mitchell

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Amyotrophic Lateral Sclerosis (ALS) is characterised by progressive motor neuron degeneration, but there is marked genetic and clinical heterogeneity1. It has been challenging to identify common ALS mechanisms among this diversity; however, a systematic framework examining motor neurons across the ALS spectrum may reveal unifying insights. Here, we present the most comprehensive compendium of ALS human induced pluripotent stem cell-derived motor neurons (iPSNs) from 429 donors, spanning 10 ALS mutations and sporadic ALS, from 15 datasets, including Answer ALS and NeuroLINCS. Using gold-standard reproducible bioinformatic workflows, we identified that ALS iPSNs show a common increase in the DNA damage response, which is characterised by activation of p53 signalling. The strongest p53 activation was observed in C9orf72 repeat expansions but was also found in TARDBP, FUS and sporadic subgroups. p53 activation was replicated in an ALS postmortem spinal cord cohort of 203 samples, indicating that the p53-dependent DNA damage response in ALS begins early and persists into the later stages of the disease. ALS iPSNs showed extensive genomic instability, as evidenced by enrichment of splicing alterations, single nucleotide variants, insertions, deletions and gene fusions, which may contribute to their p53 signature. In summary, by integrating the global landscape of ALS iPSNs, we reveal genome instability and p53 activation as common hallmarks of ALS motor neurons and provide a resource for identifying future ALS drug targets.

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Unsupervised machine learning identifies distinct molecular and phenotypic ALS subtypes in post-mortem motor cortex and blood expression data

Marriott

Kabiljo

Hunt

et al. 2023

Preprint

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Background: Amyotrophic lateral sclerosis (ALS) displays considerable clinical, genetic and molecular heterogeneity. Machine learning approaches have shown potential to disentangle complex disease landscapes and they have been utilised for patient stratification in ALS. However, lack of independent validation in different populations and in pre-mortem tissue samples have greatly limited their use in clinical and research settings. We overcame such issues by performing a large-scale study of over 600 post-mortem brain and blood samples of people with ALS from four independent datasets from the UK, Italy, the Netherlands and the US. Methods: Hierarchical clustering was performed on the 5000 most variably expressed autosomal genes identified from post-mortem motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N=112). The molecular architectures of each cluster were investigated with gene enrichment, network and cell composition analysis. Methylation and genetic data were also used to assess if other omics measures differed between individuals. Validation of these clusters was achieved by applying linear discriminant analysis models based on the KCL BrainBank to the TargetALS US motor cortex (N=93), as well as Italian (N=15) and Dutch (N=397) blood expression datasets. Phenotype analysis was also performed to assess cluster-specific differences in clinical outcomes. Results: We identified three molecular phenotypes, which reflect the proposed major mechanisms of ALS pathogenesis: synaptic and neuropeptide signalling, excitotoxicity and oxidative stress, and neuroinflammation. Known ALS risk genes were identified among the informative genes of each cluster, suggesting potential for genetic profiling of the molecular phenotypes. Cell types which are known to be associated with specific molecular phenotypes were found in higher proportions in those clusters. These molecular phenotypes were validated in independent motor cortex and blood datasets. Phenotype analysis identified distinct cluster-related outcomes associated with progression, survival and age of death. We developed a public webserver (https://alsgeclustering.er.kcl.ac.uk) that allows users to stratify samples with our model by uploading their expression data. Conclusions: We have identified three molecular phenotypes, driven by different cell types, which reflect the proposed major mechanisms of ALS pathogenesis. Our results support the hypothesis of biological heterogeneity in ALS where different mechanisms underly ALS pathogenesis in a subgroup of patients that can be identified by a specific expression signature. These molecular phenotypes show potential for stratification of clinical trials, the development of biomarkers and personalised treatment approaches.

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Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

Cited by 6 publications

References 139 publications

Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability

Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability

Genome instability underlies an augmented DNA damage response in familial and sporadic ALS human iPSC-derived motor neurons

Unsupervised machine learning identifies distinct molecular and phenotypic ALS subtypes in post-mortem motor cortex and blood expression data

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