The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
J Genet Genomics. 2022 Sep;49(9):847-858. doi: 10.1016/j.jgg.2022.03.001. Epub 2022 Mar 15.
N-methyladenosine (mA) modification, which is achieved by the METTL3/METTL14/WTAP methyltransferase complex, is the most abundant internal mRNA modification. Although recent evidence indicates that mA can regulate neurodevelopment as well as synaptic function, the roles of mA modification in the cerebellum and related synaptic connections are not well established. Here, we report that Purkinje cell (PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death. Loss of Wtap also causes the aberrant degradation of multiple PC synapses. WTAP depletion leads to decreased expression levels of METTL3/14 and reduced mA methylation in PCs. Moreover, the expression of GFAP and NF-L in the degenerating cerebellum is increased, suggesting severe neuronal injuries. In conclusion, this study demonstrates the critical role of WTAP-mediated mA modification in cerebellar PCs, thus providing unique insights related to neurodegenerative disorders.
N6-甲基腺苷（m6A）修饰是由 METTL3/METTL14/WTAP 甲基转移酶复合物完成的，是最丰富的内部 mRNA 修饰。尽管最近的证据表明 m6A 可以调节神经发育和突触功能，但 m6A 修饰在小脑和相关突触连接中的作用尚未得到充分证实。在这里，我们报告说，浦肯野细胞（PC）特异性 WTAP 敲除小鼠表现出早发性共济失调，同时伴有小脑萎缩，这是由于广泛的 PC 退化和细胞凋亡。Wtap 的缺失还导致多个 PC 突触的异常降解。WTAP 耗竭导致 METTL3/14 的表达水平降低和 PCs 中 m6A 甲基化减少。此外，变性小脑中 GFAP 和 NF-L 的表达增加，表明神经元损伤严重。总之，这项研究表明，WTAP 介导的 m6A 修饰在小脑 PCs 中起着关键作用，从而为神经退行性疾病提供了独特的见解。
