Human aminoacyl-tRNA synthetases in diseases of the nervous system

Abstract

Aminoacyl-tRNA synthetases (AaRSs) are ubiquitously expressed enzymes that ensure accurate translation of the genetic information into functional proteins. These enzymes also execute a variety of non-canonical functions that are significant for regulation of diverse cellular processes and that reside outside the realm of protein synthesis. Associations between faults in AaRS-mediated processes and human diseases have been long recognized. Most recent research findings strongly argue that 10 cytosolic and 14 mitochondrial AaRSs are implicated in some form of pathology of the human nervous system. The advent of modern whole-exome sequencing makes it all but certain that similar associations between the remaining 15 ARS genes and neurologic illnesses will be defined in future. It is not surprising that an intense scientific debate about the role of translational machinery, in general, and AaRSs, in particular, in the development and maintenance of the healthy human neural cell types and the brain is sparked. Herein, we summarize the current knowledge about causative links between mutations in human AaRSs and diseases of the nervous system and briefly discuss future directions.

The role of tRNA synthetases in neurological and neuromuscular disorders

“…Pathogenic variants of mt‐ARSs show a variety of phenotypes involving tissues with high energy demand. Despite their crucial housekeeping function and ubiquitous expression, mutations in mt‐ARSs have been implicated in a variety of paediatric and adult onset human neurological disorders of the brain, spinal cord and motor neurons in addition to disorders predominantly affecting other tissues manifesting as cardiomyopathy, myopathy, sensorineural hearing loss and endocrine symptoms . A large number of autosomal recessive disorders specifically affect the brain, and result in lesions of certain neuronal cell types.…”

“…Aminoacyl‐tRNA synthetase proteins (ARS) are a family of nuclear‐encoded enzymes that ensure correct translation of the genetic code by conjugating each of the 20 amino acids to their cognate tRNA molecule . This aminoacylation reaction provides the substrate for the protein translation process.…”

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

“…Since the discovery of aspartic tRNA synthase deficiency (DARS2) in leukodystrophies with brain stem and spinal cord involvement and lactate elevation (LBSL) in 2007 (9), there have been 14 reported pathogenic mutations that encode the mitochondrial aminoacyl-tRNA synthase gene in neurological diseases, such as mt-AlaRS (AARS2), mt-AsnRS (NARS2), mt-AspRS (DARS2), mt-ArgRS (RARS2), mt-CysRS (CARS2), mt-GluRS (EARS2), mt-HisRS (HARS2), mt-IleRS (IARS2), mt-LeuRS (LARS2), mt-MetRS (MARS2), mt-PheRS (FARS2), mt-ProRS (PARS2), mt-ThrRS (TARS2), and mt-ValRS (VARS2) (14). These mutations can induce multiple neurological disorders, such as epilepsy, autosomal recessive spastic ataxia with leukodystrophy (ARSAL), distal hereditary motor neuropathy (dHMN), hereditary motor neuropathy (HMN), LBSL, pontocerebellar hypoplasia (PCH), and leukodystrophy with thalamic and brainstem involvement and hyperlactatemia (14). However, the AARS2 mutation induces two different mutation-dependent diseases: ovarioleukodystropy (14,15) and lethal mitochondrial cardiomyopathy with lactacidosis (16).…”

Transfer RNA function and evolution

“…Given the central role of protein synthesis in all cells, defects in aminoacyl-tRNA synthesis that can cause translation defects are strongly implicated in human diseases [25]. Ognjenovic et al reviewed the role of AARSs in diseases of the nervous system [26]. Due to defects in protein synthesis and non-canonical activities of AARSs, mutations in half of the cytosolic and most of the mitochondrial AARSs are implicated in neurodegeneration or other disorders of the nervous system.…”

“…Due to defects in protein synthesis and non-canonical activities of AARSs, mutations in half of the cytosolic and most of the mitochondrial AARSs are implicated in neurodegeneration or other disorders of the nervous system. The authors highlight a number of examples illustrating the causative link between AARSs mutants and diseases, including Leukoencephalopathies, early-onset brain disorders, and sensorineural disorders [26].…”