转移RNA
突变体
蛋白质生物合成
核糖体
生物
基因
翻译(生物学)
生物化学
核糖核酸
分子生物学
化学
遗传学
细胞生物学
信使核糖核酸
作者
Amila Zuko,Moushami Mallik,Robin N Thompson,Emily L. Spaulding,Anne R. Wienand,Marije Been,Abigail L. D. Tadenev,Nick van Bakel,Céline Sijlmans,Leonardo A. Santos,Julia Bussmann,Marica Catinozzi,Sarada Das,Divita Kulshrestha,Robert W. Burgess,Zoya Ignatova,Erik Storkebaum
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2021-09-03
卷期号:373 (6559): 1161-1166
被引量:52
标识
DOI:10.1126/science.abb3356
摘要
Defeating peripheral neuropathy The mechanisms underlying peripheral neuropathies are not well understood. Spaulding et al . studied mouse models of the inherited Charcot-Marie-Tooth (CMT) disease, which is caused by mutations in transfer RNA (tRNA) synthetases. Changes in gene expression and the rate of protein synthesis in neurons in the spinal cord triggered the cell stress response activated by the protein sensor GCN2. When GCN2 was genetically deleted or inhibited with drugs, the stress response was blocked, and the neuropathy was much milder. Zuko et al . found that mutant glycyl-tRNA synthetases bind tRNA Gly but fail to release it, thus depleting the cellular tRNA Gly pool. This process caused stalling of translating ribosomes on glycine codons and activated the integrated stress response. Transgenic tRNA Gly overexpression prevented peripheral neuropathy and protein synthesis defects in mouse and fruit fly models. Thus, elevating tRNA Gly levels or targeting GCN2 may have therapeutic potential for this currently untreatable disease (see the Perspective by Mellado and Willis). —SMH
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