小柯机器人

美国约翰·霍普金斯大学Shuying Sun等研究人员合作发现，C9ORF72-ALS/FTD的N6-甲基腺苷（m6A）全面减少使RNA代谢失调并导致神经变性。2023年6月26日，《自然—神经科学》杂志在线发表了这项成果。

研究人员表示，C9ORF72的重复扩增是肌萎缩性侧索硬化症（ALS）和额颞叶痴呆症（FTD）最常见的遗传原因。

研究人员显示N6-甲基腺苷（m6A），最普遍的内部mRNA修饰，在C9ORF72-ALS/FTD患者衍生的诱导多能干细胞（iPSC）-分化的神经元和死后脑组织中被下调。全局性的m6A低甲基化导致整个转录组的mRNA稳定和基因表达上调，特别是参与突触活动和神经元功能的基因。此外，扩增重复序列上游C9ORF72内含子序列中的m6A修饰通过核阅读器YTHDC1增强了RNA的降解，反义RNA重复序列也可以通过m6A修饰来调节。m6A的减少增加了重复RNA和编码多肽的积累，有助于疾病的发病机制。

研究人员进一步证明，通过提升m6A甲基化，可以显著减少来自两条链的重复RNA水平和衍生的多肽，拯救全局mRNA平衡，并改善C9ORF72-ALS/FTD患者iPSC衍生神经元的生存。

附：英文原文

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

Author: Li, Yini, Dou, Xiaoyang, Liu, Jun, Xiao, Yu, Zhang, Zhe, Hayes, Lindsey, Wu, Rong, Fu, Xiujuan, Ye, Yingzhi, Yang, Bing, Ostrow, Lyle W., He, Chuan, Sun, Shuying

Issue&Volume: 2023-06-26

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 through m6A modification. The m6A reduction increases the accumulation of repeat RNAs and the encoded poly-dipeptides, contributing to disease pathogenesis. We further demonstrate that, by elevating m6A 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.

DOI: 10.1038/s41593-023-01374-9

Source: https://www.nature.com/articles/s41593-023-01374-9

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex