Abstract
Aminoacyl-tRNA synthetases catalyze the ligation of a specific amino acid to its cognate tRNA. The resulting aminoacyl-tRNAs are indispensable intermediates in protein biosynthesis, facilitating the precise decoding of the genetic code. Pathogenic alleles in the aminoacyl-tRNA synthetases can lead to several dominant and recessive disorders. To date, disease-specific treatments for these conditions are largely unavailable. We review pathogenic human synthetase alleles, the molecular and cellular mechanisms of tRNA synthetase diseases, and emerging approaches to allele-specific treatments, including small molecules and nucleic acid-based therapeutics. Current treatment approaches to rescue defective or dysfunctional tRNA synthetase mutants include supplementation with cognate amino acids and delivery of cognate tRNAs to alleviate bottlenecks in translation. Complementary approaches use inhibitors to target the integrated stress response, which can be dysregulated in tRNA synthetase diseases.