美国缅因州大学R. W. Burgess研究小组发现综合应激反应导致转移RNA(tRNA)合成酶相关的周围神经病变。2021年9月3日出版的《科学》发表了这项成果。

在这项研究中，研究人员使用体内细胞类型特异性转录和翻译分析证明突变tRNA合成酶通过传感器激酶GCN2（一般控制非去抑制2）激活综合应激反应(ISR)。ISR的慢性激活导致了病理生理学，药物抑制或Gcn2基因缺失减轻了周围神经病变。GCN2的激活表明突变tRNA合成酶的异常激活与翻译有关，抑制GCN2或ISR可能是腓骨肌萎缩症(CMT) 潜在的治疗策略。 

研究人员表示，tRNA合成酶基因在组织中广泛表达，其显性突变会导致轴突周围神经病变，至少六种CMT亚型是由其突变造成。小鼠和果蝇模型中的遗传证据表明存在功能获得机制。

附：英文原文

Title: The integrated stress response contributes to tRNA synthetase–associated peripheral neuropathy

Author: E. L. Spaulding, T. J. Hines, P. Bais, A. L. D. Tadenev, R. Schneider, D. Jewett, B. Pattavina, S. L. Pratt, K. H. Morelli, M. G. Stum, D. P. Hill, C. Gobet, M. Pipis, M. M. Reilly, M. J. Jennings, R. Horvath, Y. Bai, M. E. Shy, B. Alvarez-Castelao, E. M. Schuman, L. P. Bogdanik, E. Storkebaum, R. W. Burgess

Issue&Volume: 2021-09-03

Abstract: Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type–specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.

DOI: abb3414

Source: https://www.science.org/doi/10.1126/science.abb3414