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Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology

Author

Listed:
  • Oliver J. Ziff

    (The Francis Crick Institute
    University College London
    University College London NHS Foundation Trust)

  • Jacob Neeves

    (The Francis Crick Institute
    University College London)

  • Jamie Mitchell

    (The Francis Crick Institute
    University College London)

  • Giulia Tyzack

    (The Francis Crick Institute
    University College London)

  • Carlos Martinez-Ruiz

    (University College London Cancer Institute)

  • Raphaelle Luisier

    (Genomics and Health Informatics Group, Idiap Research Institute)

  • Anob M. Chakrabarti

    (The Francis Crick Institute)

  • Nicholas McGranahan

    (University College London Cancer Institute)

  • Kevin Litchfield

    (University College London Cancer Institute)

  • Simon J. Boulton

    (The Francis Crick Institute)

  • Ammar Al-Chalabi

    (Psychology and Neuroscience, King’s College London)

  • Gavin Kelly

    (The Francis Crick Institute)

  • Jack Humphrey

    (Icahn School of Medicine at Mount Sinai)

  • Rickie Patani

    (The Francis Crick Institute
    University College London
    University College London NHS Foundation Trust)

Abstract

Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.

Suggested Citation

  • Oliver J. Ziff & Jacob Neeves & Jamie Mitchell & Giulia Tyzack & Carlos Martinez-Ruiz & Raphaelle Luisier & Anob M. Chakrabarti & Nicholas McGranahan & Kevin Litchfield & Simon J. Boulton & Ammar Al-C, 2023. "Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37630-6
    DOI: 10.1038/s41467-023-37630-6
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    References listed on IDEAS

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