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 and Rickie Patani ()
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Oliver J. Ziff: The Francis Crick Institute
Jacob Neeves: The Francis Crick Institute
Jamie Mitchell: The Francis Crick Institute
Giulia Tyzack: The Francis Crick Institute
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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37630-6

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