Nagayoshi Y, Chujo T, Hirata S, Nakatsuka H, Chen C-W, Takakura M, Miyauchi K, Ikeuchi Y, Carlyle B C, Kitchen R R, Suzuki T, Katsuoka F, Yamamoto M, Goto Y, Tanaka M, Natsume K, Nairn A C, Suzuki T, Tomizawa K, Wei F-Y
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan.
Sci Adv. 2021 Mar 26;7(13). doi: 10.1126/sciadv.abf3072. Print 2021 Mar.
() gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2'--methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient-derived cells. Loss of 2'--methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNA in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.
（）基因与X连锁智力障碍（XLID）有关，但分子发病机制尚不清楚。我们发现Ftsj1负责11种胞质转移RNA（tRNA）在反密码子区域的2'-O-甲基化，而这些修饰在Ftsj1基因敲除（KO）小鼠和XLID患者来源的细胞中被消除。Ftsj1基因敲除小鼠中2'-O-甲基化的缺失选择性地降低了大脑中tRNA的稳态水平，导致苯丙氨酸密码子的解码速度减慢。核糖体分析表明，在需要有效翻译以支持突触组织和功能的一部分基因中，翻译效率显著降低。Ftsj1基因敲除小鼠表现出不成熟的突触形态和异常的突触可塑性，这与焦虑样和记忆缺陷有关。这些数据通过调节翻译效率阐明了tRNA修饰在大脑中的基本作用，并为FTSJ1相关的XLID提供了机制性见解。
