Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases.
Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases.
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DOI：
10.1038/ncomms8520
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发表时间：
2015-07-03
影响因子：
16.6
通讯作者：
Storkebaum E
中科院分区：
文献类型：
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作者：
Niehues S;Bussmann J;Steffes G;Erdmann I;Köhrer C;Sun L;Wagner M;Schäfer K;Wang G;Koerdt SN;Stum M;Jaiswal S;RajBhandary UL;Thomas U;Aberle H;Burgess RW;Yang XL;Dieterich D;Storkebaum E
五种tRNA合成酶的显性突变导致Charcot-Marie-Tooth（CMT）神经病，表明氨基酰化功能改变是该疾病的基础。然而，先前的研究表明，氨酰化活性的丧失并不是引起CMT所必需的。在这里，我们提出了一个果蝇模型CMT突变甘氨酰-tRNA合成酶（加尔斯）。三种CMT-突变加尔斯蛋白的表达诱导运动表现和运动及感觉神经元形态的缺陷，并缩短寿命。突变的加尔斯蛋白显示正常的亚细胞定位，但显着减少运动和感觉神经元中的整体蛋白质合成，或当在成人中普遍表达时，如FUNCAT和BONCAT所揭示的。翻译减慢不能归因于改变tRNAGly氨酰化，并且不能被果蝇加尔斯过表达所拯救，表明毒性功能获得机制。CMT-突变体酪氨酰-tRNA合成酶的表达也损害翻译，表明一种共同的致病机制。最后，翻译的遗传减少足以诱导CMT样表型，表明翻译减慢对CMT的因果贡献。 Charcot-Marie-Tooth（CMT）神经病与5个tRNA合成酶基因的显性突变相关。Niehues等人使用BONCAT和FUNCAT监测果蝇CMT模型中的蛋白质组动态，并揭示这些突变导致翻译减慢。
Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNAGly aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT. Charcot–Marie–Tooth (CMT) neuropathy is associated with dominant mutations in five tRNA synthetase genes. Niehues et al. use BONCAT and FUNCAT to monitor proteome dynamics in a Drosophila CMT model, and reveal that these mutations result in translational slowdown.