tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

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 gly(cyl)-tRNA synthetases bound tRNA(Gly) but failed to release it, resulting in tRNAGly 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 Drosophila 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.

Automated summary

Heterozygous mutations in six transfer RNA synthetase genes cause Charcot-Marie-Tooth peripheral neuropathy. Mutant tRNA synthetases in CMT inhibit protein synthesis by binding tRNA(Gly) but failing to release it, leading to tRNAGly sequestration and ribosome stalling. Overexpression of tRNA(Gly) rescues protein synthesis, peripheral neuropathy, and ISR activation, suggesting therapeutic potential in CMT2D.