Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability

Abstract

Amyotrophic Lateral Sclerosis (ALS) is characterised by progressive motor neuron degeneration but there is marked genetic and clinical heterogeneity1. Identifying common mechanisms of ALS amongst this diversity has been challenging, however, a systematic framework examining motor neurons across the ALS spectrum may reveal unifying insights. Here, we present the most comprehensive compendium of ALS human-induced pluripotent stem cell-derived motor neurons (iPSNs) from 429 donors across 15 datasets including Answer ALS and NeuroLINCS, spanning 10 ALS mutations and sporadic ALS. Using gold-standard reproducible bioinformatic workflows, we identify that ALS iPSNs show common activation of the DNA damage response and p53 signalling, which was replicated in the NYGC ALS postmortem cohort of 203 spinal cord samples. The strongest p53 activation was observed in C9orf72 repeat expansions but was also independently increased in TARDBP, FUS and sporadic subgroups. ALS iPSNs showed extensive splicing alterations and enrichment of SNVs, indels and gene fusions, which may contribute to their damage-induced mutation signature. Our results integrate the global landscape of motor neuron alterations in ALS, revealing that genome instability is a common hallmark of ALS motor neurons and provides a resource to identify future ALS drug targets.

WITHDRAWN: Circular RNA expression in ALS is progressively deregulated and tissue-dependent

“…Although the degradation of circRNAs has hardly been studied, it has recently been shown that m6a methylation of RNA and activity of RNase L could promote the global elimination of circRNAs [3]. Interestingly, m6a hypermethylation of protein coding and non-coding RNA species have been observed in the spinal cord of sALS patients [78] and the expression of RNase L transcript is upregulated in iPSC-derived motor neurons from ALS patients [79]. In this respect, RNase L-mediated degradation of circRNA has been found to be necessary for the activation of protein kinase R (PKR) [80], which has been detected at higher levels in spinal cord [81] as well as in hippocampus from ALS patients [82], and its inhibition has been proposed as a promising therapeutic approach [82].…”