Stressing out translation

Many Charcot-Marie-Tooth (CMT) disease–causing mutations occur in the genes encoding aminoacyl–transfer RNA (tRNA) synthetases (AARSs), leading to peripheral sensory and motor neuropathy. AARSs are responsible for implementing the genetic code: They catalyze the initial reaction of protein translation, charging the tRNA with its respective amino acid (1). One of the putative causes of this disease is the inhibition of global protein synthesis; however, the underlying mechanism or mechanisms are unknown, although studies suggest that it is independent of aminoacylation activity. On pages 1156 and 1161 of this issue, Spaulding et al. (2) and Zuko et al. (3), respectively, demonstrate that CMT neurons have altered translational profiles and aberrant AARS-tRNA binding, which causes depletion of available aminoacyl tRNAs, resulting in activation of the integrated stress response (ISR) and leading to neuropathy. Taken together, these results point to a compelling model that can explain how dominantly inherited mutations in multiple AARSs result in similar CMT disease.