| First Author | Spaulding EL | Year | 2021 |
| Journal | Science | Volume | 373 |
| Issue | 6559 | Pages | 1156-1161 |
| PubMed ID | 34516839 | Mgi Jnum | J:310162 |
| Mgi Id | MGI:6761366 | Doi | 10.1126/science.abb3414 |
| Citation | Spaulding EL, et al. (2021) The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science 373(6559):1156-1161 |
| abstractText | 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 typeâspecific 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. |
