Determining transcriptome changes in whole spinal cord of YarsE196K mice [19-burgess-002]

To determine transcriptome changes in adult spinal cord induced by the YarsE196K mutation. How mutations in broadly expressed housekeeping genes lead to neurodegeneration in specific cell types remains unclear. Mutations in ubiquitously expressed tRNA synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth disease. Genetic evidence in mouse and Drosophila models suggests a neomorphic gain-of-function mechanism. Here, we use in vivo, cell-type-specific transcriptional and translational profiling of affected peripheral neurons to show that mutant tRNA synthetases impair translation and activate the integrated stress response (ISR) through the sensor kinase, GCN2. The chronic activation of the ISR contributes to the pathophysiology, and genetic deletion of Gcn2 alleviates the peripheral neuropathy. The activation of GCN2 by tRNA synthetase mutations indicates their neomorphic activity is still related to translation and suggests inhibiting GCN2 or the ISR as a therapeutic strategy. Whole spinal cord RNA sequencing was performed on WT, YarsE196K heterozygous, and YarsE196K homozygous 7 month-old mice and differential expression analysis was run.