Globally reduced N 6 -methyladenosine (m 6 A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration.
Yini LiXiaoyang DouJun LiuYu XiaoZhe ZhangLindsey R HayesRong WuXiujuan FuYingzhi YeBing YangLyle W OstrowChuan HeShuying SunPublished in: Nature neuroscience (2023)
Repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we show that N 6 -methyladenosine (m 6 A), the most prevalent internal mRNA modification, is downregulated in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons and postmortem brain tissues. The global m 6 A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, particularly for genes involved in synaptic activity and neuronal function. Moreover, the m 6 A modification in the C9ORF72 intron sequence upstream of the expanded repeats enhances RNA decay via the nuclear reader YTHDC1, and the antisense RNA repeats can also be regulated through m 6 A modification. The m 6 A reduction increases the accumulation of repeat RNAs and the encoded poly-dipeptides, contributing to disease pathogenesis. We further demonstrate that, by elevating m 6 A methylation, we could significantly reduce repeat RNA levels from both strands and the derived poly-dipeptides, rescue global mRNA homeostasis and improve survival of C9ORF72-ALS/FTD patient iPSC-derived neurons.
Keyphrases
- amyotrophic lateral sclerosis
- gene expression
- stem cells
- genome wide
- nucleic acid
- dna methylation
- spinal cord
- binding protein
- high glucose
- transcription factor
- white matter
- case report
- diabetic rats
- cerebral ischemia
- resting state
- functional connectivity
- mesenchymal stem cells
- endothelial cells
- cell therapy
- amino acid
- oxidative stress
- stress induced