Samuels Tristan N, Wu Fanqi, Mahmood Maria, Abuzaid Wajd A, Sun Nancy, Moresco Angelica, Siu Victoria M, O'Donoghue Patrick, Heinemann Ilka U
Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Canada.
Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, Canada.
FEBS J. 2025 Jun;292(11):2737-2750. doi: 10.1111/febs.17361. Epub 2024 Dec 19.
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.
氨酰-tRNA合成酶催化特定氨基酸与其对应的tRNA连接。由此产生的氨酰-tRNA是蛋白质生物合成中不可或缺的中间体，有助于精确解码遗传密码。氨酰-tRNA合成酶中的致病等位基因可导致多种显性和隐性疾病。迄今为止，针对这些病症的疾病特异性治疗方法在很大程度上尚不存在。我们综述了致病性人类合成酶等位基因、tRNA合成酶疾病的分子和细胞机制，以及新兴的等位基因特异性治疗方法，包括小分子和基于核酸的疗法。目前拯救有缺陷或功能失调的tRNA合成酶突变体的治疗方法包括补充同源氨基酸和递送同源tRNA以缓解翻译瓶颈。补充方法使用抑制剂来靶向整合应激反应，这种反应在tRNA合成酶疾病中可能失调。
