Mathoux Justine, Wilson Marc-Michel, Srinivas Sujithra, Litovskich Gabrielle, Villalba Benito Leticia, Tran Cindy, Kesavan Jaideep, Harnett Aileen, Auer Theresa, Sanz-Rodriguez Amaya, Kh A E Alkhayyat Mohammad, Sullivan Mairéad, Liu Zining, Huang Yifan, Lacey Austin, Delanty Norman, Cryan Jane, Brett Francesca M, Farrell Michael A, O'Brien Donncha F, Casillas-Espinosa Pablo M, Jimenez-Mateos Eva M, Glennon Jeffrey C, Canavan Mary, Henshall David C, Brennan Gary P
Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
FutureNeuro Research Ireland Centre for Translational Brain Science, and.
JCI Insight. 2025 Jul 22;10(14). doi: 10.1172/jci.insight.188612.
Analogous to DNA methylation and protein phosphorylation, it is now well understood that RNA is also subject to extensive processing and modification. N6-methyladenosine (m6A) is the most abundant internal RNA modification and regulates RNA fate in several ways, including stability and translational efficiency. The role of m6A in both experimental and human epilepsy remains unknown. Here, we used transcriptome-wide m6A arrays to obtain a detailed analysis of the hippocampal m6A-ome from both mouse and human epilepsy samples. We combined this with human proteomic analyses and show that epileptic tissue displays disrupted metabolic and autophagic pathways that may be directly linked to m6A processing. Specifically, our results suggest that m6A levels inversely correlate with protein pathway activation. Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice. Together, our findings indicate that m6A represents an additional layer of gene regulation complexity in epilepsy and may contribute to the pathomechanisms that drive the development and maintenance of hyperexcitable brain networks.
与DNA甲基化和蛋白质磷酸化类似，现在人们已经充分认识到RNA也会经历广泛的加工和修饰。N6-甲基腺苷（m6A）是最丰富的内部RNA修饰，它通过多种方式调节RNA的命运，包括稳定性和翻译效率。m6A在实验性癫痫和人类癫痫中的作用仍然未知。在这里，我们使用全转录组m6A阵列对小鼠和人类癫痫样本的海马m6A组进行了详细分析。我们将此与人类蛋白质组学分析相结合，表明癫痫组织中代谢和自噬途径受到破坏，这可能与m6A加工直接相关。具体而言，我们的结果表明m6A水平与蛋白质途径激活呈负相关。最后，我们表明m6A水平升高会降低小鼠的癫痫易感性和严重程度。总之，我们的研究结果表明，m6A代表了癫痫中基因调控复杂性的一个额外层面，可能有助于驱动高兴奋性脑网络发展和维持的病理机制。
