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

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 studi es 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. AbstractCharcot ‐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 enzym es 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 a ctivity 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 aaRS...

Source: Journal of Neurochemistry - December 19, 2020 Category: Neuroscience Authors: Han Zhang, Zhong ‐Wei Zhou, Litao Sun Tags: Review Source Type: research