Abstract:
N6-methyladenosine (m6A) modification, which is achieved by the METTL3/METTL14/WTAP methyltransferase complex, is the most abundant internal mRNA modification. Although recent evidence indicates that m6A can regulate neurodevelopment as well as synaptic function, the roles of m6A 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 m6A 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 m6A modification in cerebellar PCs, thus providing unique insights related to neurodegenerative disorders.
摘要:
N6-甲基腺苷(m6A)修饰,这是由METTL3/METTL14/WTAP甲基转移酶复合物实现的,是最丰富的内部mRNA修饰。尽管最近的证据表明m6A可以调节神经发育以及突触功能,m6A修饰在小脑和相关突触连接中的作用尚未明确。这里,我们报道,Purkinje细胞(PC)特异性WTAP基因敲除小鼠表现出早发性共济失调并伴有大范围PC变性和凋亡性细胞死亡所致的小脑萎缩.Wtap的丢失还导致多个PC突触的异常降解。WTAP消耗导致PC中METTL3/14的表达水平降低和m6A甲基化降低。此外,变性小脑中GFAP和NF-L的表达增加,提示严重的神经元损伤。总之,这项研究证明了WTAP介导的m6A修饰在小脑PCs中的关键作用,从而提供了有关神经退行性疾病的独特见解。