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N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_total_RNA-MeRIP]

ABSTRACT: N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_total_RNA-MeRIP]

PROVIDER: PRJNA841494 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19355547_1.fastq.gz	Fastqsanger.gz
	SRR19355547_2.fastq.gz	Fastqsanger.gz
	SRR19355548_1.fastq.gz	Fastqsanger.gz
	SRR19355548_2.fastq.gz	Fastqsanger.gz
	SRR19355549_1.fastq.gz	Fastqsanger.gz

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N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_total_RNA-MeRIP]

Project description:N6-methyladenosine (m6A) is the most prevalent internal mRNA modification and regulates RNA metabolism. Repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Here, we showed that m6A is downregulated in C9ORF72-ALS/FTD patient-derived iPSC-differentiated neurons and postmortem brain tissues. The global m6A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, especially ones involved in synaptic activity and neuronal functions. The m6A modification in the C9ORF72 intron sequence preceding the expanded repeats enhances RNA degradation via the nuclear reader YTHDC1. The m6A reduction leads to increased accumulation of repeat RNA and poly-dipeptides. Moreover, the antisense RNA can also be regulated by m6A. Elevating m6A level significantly reduces both sense and antisense repeat RNA and poly-dipeptides, rescues global mRNA homeostasis, and improves survival of C9ORF72-ALS/FTD patient neurons.

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N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_polyA_RNA-RIP]

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Poly-GR impairs translation elongation and increases ribotoxic stress response in C9ORF72-ALS/FTD

Project description:Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-GR is one of the most toxic dipeptide repeat (DPR) proteins translated from the RNA repeats. It has been shown to affect protein synthesis, but how this contributes to neurodegeneration is not clear. Here, we found that poly-GR inhibits global translation by perturbing translation elongation. We identified that the transcripts with relatively slow elongation rate tend to be further stalled by poly-GR in iPSC-differentiated neurons. This increases ribosome collision and ZAKα-mediated ribotoxic stress response (RSR), which elevates the phosphorylation of p38 and promotes cell death. Knockdown of ZAKα or pharmacological inhibition of p38 can ameliorate the GR toxicity, and improve the survival of C9ORF72-ALS/FTD patient-derived iPSC-neurons. Our study reveals molecular mechanism of poly-GR mediated toxicity on global translatome, and identifies RSR as a potential therapeutic target for C9ORF72-ALS/FTD.

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N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_polyA_RNA-RIP]

Project description:N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_polyA_RNA-RIP]

| PRJNA841493 | ENA