Globally reduced N⁶-methyladenosine (m⁶A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration.

ABSTRACT: Repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we show that N⁶-methyladenosine (m⁶A), 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 m⁶A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, particularly for genes involved in synaptic activity and neuronal function. Moreover, the m⁶A 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 thro

SUBMITTER: Li Y 

PROVIDER: S-EPMC11361766 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature