Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
Oliver J. Ziff, Jacob Neeves, Jamie S. Mitchell, Giulia E. Tyzack, Carlos Martínez‐Ruiz, Raphaëlle Luisier, Anob M. Chakrabarti, Nicholas McGranahan, Kevin Litchfield, Simon J. Boulton, Ammar Al‐Chalabi, Gavin Kelly, Jack Humphrey, Rickie Patani
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.