tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Abstract

Heterozygous mutations in six transfer RNA (tRNA) synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT mutant tRNA synthetases inhibit protein synthesis by an unknown mechanism. We found that CMT mutant glycyl-tRNA synthetases bound tRNA^Gly but failed to release it, resulting in tRNA^Gly sequestration. This sequestration potentially depleted the cellular tRNA^Gly pool, leading to insufficient glycyl-tRNA^Gly supply to the ribosome. Accordingly, we found ribosome stalling at glycine codons and activation of the integrated stress response (ISR) in affected motor neurons. Moreover, transgenic overexpression of tRNA^Gly rescued protein synthesis, peripheral neuropathy, and ISR activation in <i>Drosophila</i> and mouse CMT disease type 2D (CMT2D) models. Conversely, inactivation of the ribosome rescue factor GTPBP2 exacerbated peripheral neuropathy. Our findings suggest a molecular mechanism for CMT2D, and elevating tRNA^Gly levels may thus have therapeutic potential.