Banks, G.T.; Bros-Facer, V.; Williams, H.P.; Chia, R.; Achilli, F.; Bryson, J.B.; Greensmith, L.; Banks, G.T.; Bros-Facer, V.; Williams, H.P.; Chia, R.; Achilli, F.; Bryson, J.B.; Greensmith, L.; Fisher, E.M.C.; - view fewer (2009) Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1G93A motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice. PLoS ONE , 4 (7) , Article e6218. 10.1371/journal.pone.0006218.

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Abstract

Background: In humans, mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system, and clinical phenotypes ranging from Charcot-Marie-Tooth neuropathy to a severe infantile form of spinal muscular atrophy. GARS is ubiquitously expressed and may have functions in addition to its canonical role in protein synthesis through catalyzing the addition of glycine to cognate tRNAs. Methodology/Principal findings: We have recently described a new mouse model with a point mutation in the Gars gene resulting in a cysteine to arginine change at residue 201. Heterozygous Gars^{C201R/+} mice have locomotor and sensory deficits. In an investigation of genetic mutations that lead to death of motor and sensory neurons, we have crossed the Gars^{C201R/+} mice to two other mutants: the TgSOD1^{G93A} model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1^{Loa}) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1^{Loa/+}; Gars^{C201R/+} double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the Gars^{C201R} mutation significantly delayed disease onset in the SOD1^{G93A}; Gars^{C201R/+} double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated. Conclusions/Significance: These findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains.

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