Libera Jenna L, Hu Junming, Nguyen Tuyet-Anh, Wang Zihan, van der Spek Sophie J F, Schult Kamryn, Dorrian Luke, Majka Jordan, Tobunluepop Katarnut, Puri Sambhavi, Kynshov Alexander, Kanaan Nicholas M, Nelson Peter T, Meyer Kate, Hou Lei, Zhang Xiaoling, Wolozin Benjamin
Department of Anatomy and Neurobiology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA.
Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA.
bioRxiv. 2025 May 7:2025.05.02.651974. doi: 10.1101/2025.05.02.651974.
Dysregulated RNA metabolism is a significant feature of Alzheimer's disease (AD), yet how post-transcriptional RNA modifications like -methyladenosine (mA) are altered in AD is unknown. Here, we performed deamination adjacent to RNA modification targets (DART-seq) on human dorsolateral prefrontal cortices to assess changes in mA with nucleotide resolution. In non-AD brains, mA sites increased with age, predominantly within the 3'UTR of transcripts encoding tripartite synapse proteins. In contrast, AD brains lost the age-associated mA site increase and exhibited global hypomethylation of transcripts, including and . Hypomethylated genes involved with GABAergic signaling, glutamate transport, and ubiquitin-mediated proteolysis exhibited reduced expression, connecting mA to synaptic excitotoxicity and disrupted proteostasis in AD. Site-specific mA levels were linked with expression and protein levels, but this relationship was abolished in AD. Our findings provide insight into post-transcriptional mechanisms of dysregulated RNA metabolism in AD that are related to aging and GABAergic regulation.
RNA代谢失调是阿尔茨海默病（AD）的一个显著特征，但像N6-甲基腺苷（m6A）这样的转录后RNA修饰在AD中是如何改变的尚不清楚。在这里，我们对人类背外侧前额叶皮质进行了邻近RNA修饰靶点的脱氨基作用（DART-seq），以在核苷酸分辨率下评估m6A的变化。在非AD大脑中，m6A位点随年龄增加，主要在编码三方突触蛋白的转录本的3'UTR内。相比之下，AD大脑失去了与年龄相关的m6A位点增加，并表现出转录本的整体低甲基化，包括[此处缺失具体基因名称]和[此处缺失具体基因名称]。参与GABA能信号传导、谷氨酸转运和泛素介导的蛋白水解的低甲基化基因表达降低，将m6A与AD中的突触兴奋性毒性和蛋白稳态破坏联系起来。位点特异性m6A水平与[此处缺失具体基因名称]表达和蛋白质水平相关，但这种关系在AD中被消除。我们的研究结果为AD中与衰老和GABA能调节相关的RNA代谢失调的转录后机制提供了见解。
