Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, Nijmegen, Netherlands.
Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Science. 2021 Sep 3;373(6559):1161-1166. doi: 10.1126/science.abb3356. Epub 2021 Sep 1.
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 tRNA but failed to release it, resulting in tRNA sequestration. This sequestration potentially depleted the cellular tRNA pool, leading to insufficient glycyl-tRNA 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 tRNA rescued protein synthesis, peripheral neuropathy, and ISR activation in 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 tRNA levels may thus have therapeutic potential.
六种转移 RNA（tRNA）合成酶基因中的杂合突变导致 Charcot-Marie-Tooth（CMT）周围神经病。CMT 突变 tRNA 合成酶通过未知机制抑制蛋白质合成。我们发现 CMT 突变甘氨酰-tRNA 合成酶结合 tRNA 但未能释放它，导致 tRNA 隔离。这种隔离可能耗尽了细胞内的 tRNA 池，导致核糖体缺乏足够的甘氨酰-tRNA 供应。因此，我们发现核糖体在甘氨酸密码子处停滞，并且在受影响的运动神经元中激活了整合应激反应（ISR）。此外，在 和 小鼠 CMT2D 模型中转基因过表达 tRNA 可挽救蛋白质合成、周围神经病和 ISR 激活。相反，核糖体挽救因子 GTPBP2 的失活使周围神经病恶化。我们的研究结果为 CMT2D 提供了一种分子机制，并且提高 tRNA 水平可能因此具有治疗潜力。
