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

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-Chalabi, Gavin Kelly, Jack Humphrey, Rickie Patani

    Research output: Contribution to journalArticlepeer-review

    15 Scopus citations


    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.

    Original languageEnglish
    Article number2176
    JournalNature Communications
    Issue number1
    StatePublished - Dec 2023


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