Aminoacyl‐tRNA synthetases in Charcot–Marie–Tooth disease: A gain or a loss?

• Published in: Journal of neurochemistry Vol. 157; no. 3; pp. 351 - 369
• Main Authors: Zhang, Han, Zhou, Zhong‐Wei, Sun, Litao
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2021; John Wiley and Sons Inc
• Subjects: Amino acids; Aminoacylation; aminoacyl‐tRNA synthetases; animal model; Charcot-Marie-Tooth disease; Conformational analysis; Enzymatic activity; Genetic analysis; mutation; Neurodegenerative diseases; Pathogenesis; Protein biosynthesis; Protein synthesis; Proteins; Review; tRNA; mutation; pathogenesis; charcot-marie-tooth disease; aminoacyl-tRNA synthetases; animal model
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15249

Charcot‐Marie‐Tooth disease (CMT) is one of the most common inherited neurodegenerative disorders with an increasing number of CMT‐associated variants identified as causative factors, however, there has been no effective therapy for CMT to date. Aminoacyl‐tRNA synthetases (aaRS) are essential enzymes in translation by charging amino acids onto their cognate tRNAs during protein synthesis. Dominant monoallelic variants of aaRSs have been largely implicated in CMT. Some aaRSs variants affect enzymatic activity, demonstrating a loss‐of‐function property. In contrast, loss of aminoacylation activity is neither necessary nor sufficient for some aaRSs variants to cause CMT. Instead, accumulating evidence from CMT patient samples, animal genetic studies or protein conformational analysis has pinpointed toxic gain‐of‐function of aaRSs variants in CMT, suggesting complicated mechanisms underlying the pathogenesis of CMT. In this review, we summarize the latest advances in studies on CMT‐linked aaRSs, with a particular focus on their functions. The current challenges, future direction and the promising candidates for potential treatment of CMT are also discussed. Variants of some aminoacyl‐tRNA synthetases (aaRS) are strongly associated with Charcot–Marie–Tooth disease (CMT), one of the most common inherited neuromuscular disorders. Some variants affect enzymatic activity, showing loss‐of‐function effects. In contrast, evidence from CMT patient samples, animal genetic studies or protein conformational analysis has confirmed toxic gain‐of‐function of some aaRSs variants in CMT outside of aminoacylation. In this review, we will discuss the latest advances in studies on CMT‐associated aaRSs, with a particular focus on the complicated mechanisms in the pathogenesis of CMT.