Contractors get lots of business from do-it-yourself consumers who have learned unfortunate lessons about the value of quality construction. Proper construction is also important for proteins in cells. Transfer RNA (tRNA) translates individual mRNA codons into amino acids. Aminoacyl tRNA synthetases link the appropriate amino acid to tRNA in a process called aminoacylation. Two research groups report neurological phenotypes in mice with mutations in aminoacyl tRNA synthetases in recent articles in Nature and Neuron.
Lee et al. report that a loss-of-function mutation in an aminoacyl tRNA synthetase causes neurodegeneration. Mice with the 'sticky' mutation have sticky-looking fur and a neurological phenotype that includes tremors, ataxia and Purkinje cell loss. The authors mapped the 'sticky' mutation to a point mutation in Aars, which encodes alanyl tRNA synthetase (AlaRS).
The mutation localizes to the editing domain of AlaRS, which hydrolizes incorrectly attached amino acids. Aminoacylation was normal, but editing of misacylated tRNAs was compromised in mice with the sticky mutation. The authors found tRNAs coding for alanine but acylated to serine in mouse embryonic fibroblasts expressing mutant AlaRS.
Proteins with errors fold incorrectly and induce an unfolded protein stress response in the cell. Serine caused a dose-dependent increase in cell death in fibroblasts expressing mutant AlaRS. Sticky mice had protein inclusion bodies in Purkinje cells and increased expression of transcription factors induced by the unfolded protein response. Therefore, the authors concluded that Purkinje cell death in sticky mice is caused by accumulations of proteins with sequence errors.
Seburn et al. report that a gain-of-function mutation in an aminoacyl tRNA synthetase gene causes neuropathy. Using a mutagenesis screen, the authors identified Nmf249, a dominantly inherited mutation that caused neuromuscular dysfunction by three and death by eight weeks of age. They mapped the mutation to the Gars gene, which encodes glycyl tRNA synthetase (GlyRS) and is associated with the progressive axonopathy disease Charcot-Marie-Tooth disease type 2D.
Consistent with type 2 Charcot-Marie-Tooth disease, mice heterozygous for the Nmf249 mutation (GarsNmf249/+) had progressive neuropathy. By 37 days of age, approximately 32% of GarsNmf249/+ neuromuscular junctions were partially innervated and roughly 20% were totally denervated. The authors found more severe defects in distal than in proximal nerves. Distal nerve impulse conduction was 60% slower in GarsNmf249/+ relative to wild-type mice. In 35 day-old GarsNmf249/+ mice, the authors were unable to find any large-diameter peripheral axons, which innervate large leg muscles.
The mutation in GarsNmf249 was located near the catalytic domain of GlyRS. However, GlyRS aminoacylation was similar in GarsNmf249/+ and wild-type mice. In contrast, a Gars hypomorph had no neuromuscular dysfunction, but showed compromised GlyRS aminoacylation. Therefore, the authors concluded that GarsNmf249 causes neuromuscular dysfunction through a toxic gain-of-function rather than a loss of GlyRS activity.
Together, these data indicate that mutations in aminoacyl tRNA synthetases particularly affect the nervous system and suggest that they may be important targets for gene therapy in neurological disease.