Integrated Transcriptome Landscape of ALS Identifies Genome Instability Linked to TDP-43 Pathology

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Apr 20

PMID 37080969

Authors

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

Affiliations

Soon will be listed here.

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.

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