Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability.
Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability.
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Ftsj1的缺失扰乱大脑中密码子特异性翻译效率，并与X连锁智力残疾相关。
DOI：
10.1126/sciadv.abf3072
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发表时间：
2021-03
期刊：
影响因子：
13.6
通讯作者：
Wei FY
中科院分区：
文献类型：
--
作者：
Nagayoshi Y;Chujo T;Hirata S;Nakatsuka H;Chen CW;Takakura M;Miyauchi K;Ikeuchi Y;Carlyle BC;Kitchen RR;Suzuki T;Katsuoka F;Yamamoto M;Goto Y;Tanaka M;Natsume K;Nairn AC;Suzuki T;Tomizawa K;Wei FY
TRNA2‘-O修饰缺陷会降低脑内Phe密码子的翻译效率，导致神经功能障碍。FtsJ RNA2‘-O-甲基转移酶1(FTSJ1)基因与X-连锁智能障碍(XLID)有关，但其分子发病机制尚不清楚。我们发现Ftsj1负责11种胞浆转移RNA(TRNAs)反密码子区域的2‘-O-甲基化，并且这些修改在Ftsj1基因敲除(KO)小鼠和XLID患者来源的细胞中被取消。Ftsj1KO小鼠2‘-O-甲基化的缺失选择性地降低了大脑中tRNAPhe的稳态水平，导致Phe密码子的解码速度缓慢。核糖体图谱显示，需要有效翻译以支持突触组织和功能的基因子集的翻译效率显著降低。Ftsj1KO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。这些数据阐明了tRNA修饰通过调节翻译效率在大脑中的基础作用，并提供了对FTSJ1相关XLID的机械性见解。
Defective tRNA 2′-O-modification impairs translation efficiency at Phe codon in the brain and induces a neurological dysfunction. FtsJ RNA 2′-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2′-O-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′-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe 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.
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DOI：
10.1261/rna.047639.114
发表时间：
2015-01
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Guy MP;Phizicky EM
通讯作者：
Phizicky EM
影响因子：
14.9
作者：
Chan PP;Lowe TM
通讯作者：
Lowe TM
从杏仁核中的电路到行为。
影响因子：
64.8
作者：
Janak PH;Tye KM
通讯作者：
Tye KM
影响因子：
3.9
作者：
Guy MP;Shaw M;Weiner CL;Hobson L;Stark Z;Rose K;Kalscheuer VM;Gecz J;Phizicky EM
通讯作者：
Phizicky EM
影响因子：
4.5
作者：
Konevega, AL;Soboleva, NG;Katunin, VI
通讯作者：
Katunin, VI