The integrated stress response contributes to tRNA synthetase–associated peripheral neuropathy

Defeating peripheral neuropathy The mechanisms underlying peripheral neuropathies are not well understood. Spauldinget 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. Zukoet al . found that mutant glycyl-tRNA synthetases bind tRNAGly but fail to release it, thus depleting the cellular tRNAGly pool. This process caused stalling of translating ribosomes on glycine codons and activated the integrated stress response. Transgenic tRNAGly overexpression prevented peripheral neuropathy and protein synthesis defects in mouse and fruit fly models. Thus, elevating tRNAGly levels or targeting GCN2 may have therapeutic potential for this currently untreatable disease (see the Perspective by Mellado and Willis). —SMH