GARS axonopathy: not every neuron's cup of tRNA

Abstract

Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work.

Figure 1

The GARS transcript produces two protein products, a cytosolic isoform and a mitochondrial isoform that has a 54 amino acid mitochondrial targeting sequence. The remaining 685 amino acids encoded by the transcript are shared by both isoforms. The mutations that have been identified in GARS (black, human; red, mouse) are distributed across the entire protein in all of the functional domains. Many of the mutations that have been identified lie in one of the three regions that form the dimer interface.

Figure 2

Possible mechanisms by which mutations in GARS could be leading to axon degeneration in these uniquely shaped cells. Some of these are unlikely or have been ruled out by functional analysis ((1) Loss of charging function, (2) Aggregation, (3) Mischarging), others require further investigation ((4) Nucleolar dysfunction, (5) Dimerization, (6) Non-canonical functions, (7) novel interactions resulting from mutations, (8) Mitochondrial toxicity or dysfunction, (9) Impaired axonal transport that lead to deficits in local translation).