An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations.
Animals, Axons, Charcot-Marie-Tooth-Disease, Disease-Models-Animal, Femoral-Nerve, Immunohistochemistry, Mice-Inbred-C57BL, Mice-Mutant-Strains, Microscopy-Confocal, Mutation, Nerve-Degeneration, Neuromuscular-Junction, Peripheral-Nervous-System-Diseases, Phenotype, Protein-Biosynthesis, Purkinje-Cells
Mol Cell Neurosci 2011; 46(2):432-43.
Mutations in glycyl-, tyrosyl-, and alanyl-tRNA synthetases (GARS, YARS and AARS respectively) cause autosomal dominant Charcot-Marie-Tooth disease, and mutations in Gars cause a similar peripheral neuropathy in mice. Aminoacyl-tRNA synthetases (ARSs) charge amino acids onto their cognate tRNAs during translation; however, the pathological mechanism(s) of ARS mutations remains unclear. To address this, we tested possible mechanisms using mouse models. First, amino acid mischarging was discounted by examining the recessive "sticky" mutation in alanyl-tRNA synthetase (Aars(sti)), which causes cerebellar neurodegeneration through a failure to efficiently correct mischarging of tRNA(Ala). Aars(sti/sti) mice do not have peripheral neuropathy, and they share no phenotypic features with the Gars mutant mice. Next, we determined that the Wallerian Degeneration Slow (Wlds) mutation did not alter the Gars phenotype. Therefore, no evidence for misfolding of GARS itself or other proteins was found. Similarly, there were no indications of general insufficiencies in protein synthesis caused by Gars mutations based on yeast complementation assays. Mutant GARS localized differently than wild type GARS in transfected cells, but a similar distribution was not observed in motor neurons derived from wild type mouse ES cells, and there was no evidence for abnormal GARS distribution in mouse tissue. Both GARS and YARS proteins were present in sciatic axons and Schwann cells from Gars mutant and control mice, consistent with a direct role for tRNA synthetases in peripheral nerves. Unless defects in translation are in some way restricted to peripheral axons, as suggested by the axonal localization of GARS and YARS, we conclude that mutations in tRNA synthetases are not causing peripheral neuropathy through amino acid mischarging or through a defect in their known function in translation.
Stum, M; McLaughlin, H M.; Kleinbrink, E L.; Miers, K E.; Ackerman, S L.; Seburn, K L.; Antonellis, A; and Burgess, R W., "An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations." (2011). Faculty Research 2011. 7.