近日，荷兰拉德堡德大学Erik Storkebaum团队发现，tRNA过表达可挽救由tRNA合成酶突变引起的周围神经病变。这一研究成果发表在2021年9月3日出版的国际学术期刊《科学》上。

据研究人员介绍，六个转移RNA（tRNA）合成酶基因的杂合突变导致Charcot-Marie-Tooth（CMT）周围神经病变。CMT突变的tRNA合成酶通过一种未知的机制抑制蛋白质的合成。

研究人员发现，CMT突变体甘氨酰-tRNA合成酶与tRNAGly结合但不能释放，导致tRNA^Gly被禁锢。这种禁锢可能会耗尽细胞中的tRNA^Gly池，导致核糖体中的甘氨酰-tRNA^Gly供应不足。因此，研究人员发现在受影响的运动神经元中，核糖体在甘氨酸密码子处停滞，并激活了综合应激反应（ISR）。

此外，tRNA^Gly的转基因过表达挽救了果蝇和小鼠CMT疾病2D型（CMT2D）模型的蛋白质合成、周围神经病变和ISR的激活。相反，核糖体拯救因子GTPBP2的失活则加剧了周围神经病变。这些发现揭示了CMT2D的分子机制，因此提高tRNA^Gly水平可能具有治疗潜力。

附：英文原文

Title: tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Author: Amila Zuko, Moushami Mallik, Robin 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

Issue&Volume: 2021-09-03

Abstract: Heterozygous mutations in six transfer RNA (tRNA) synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT mutant tRNA synthetases inhibit protein synthesis by an unknown mechanism. We found that CMT mutant glycyl-tRNA synthetases bound tRNAGly but failed to release it, resulting in tRNAGly sequestration. This sequestration potentially depleted the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome. Accordingly, we found ribosome stalling at glycine codons and activation of the integrated stress response (ISR) in affected motor neurons. Moreover, transgenic overexpression of tRNAGly rescued protein synthesis, peripheral neuropathy, and ISR activation in Drosophila and mouse CMT disease type 2D (CMT2D) models. Conversely, inactivation of the ribosome rescue factor GTPBP2 exacerbated peripheral neuropathy. Our findings suggest a molecular mechanism for CMT2D, and elevating tRNAGly levels may thus have therapeutic potential.

DOI: abb3356

Source: https://www.science.org/doi/10.1126/science.abb3356