tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

作者：Amila Zuko, Moushami Mallik, Robin Thompson, Emily L. Spaulding, Anne Wienand, Marije Been, Abigail L. D. Tadenev, Nick van Bakel, Céline Sijlmans, Leonardo A. Santos, Julia Bussmann, Marica Catinozzi, Sarada Das, Divita Kulshrestha, Robert Wilbur Burgess, Zoya Ignatova, Erik Storkebaum · 发表于：Science · 年份：2021 · DOI：10.1126/science.abb3356 · 被引用次数：131 · 研究领域：RNA and protein synthesis mechanisms、RNA modifications and cancer、RNA Research and Splicing

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