Mutant Glycyl-tRNA Synthetase (Gars) Ameliorates SOD1G93A Motor Neuron Degeneration Phenotype but Has Little Affect on Loa Dynein Heavy Chain Mutant Mice

Abstract

BackgroundIn 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 FindingsWe 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 GarsC201R/+ 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 GarsC201R/+ mice to two other mutants: the TgSOD1G93A model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1Loa) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1Loa/+;GarsC201R/+ double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the GarsC201R mutation significantly delayed disease onset in the SOD1G93A;GarsC201R/+ double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated.Conclusions/SignificanceThese findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains.

Cytoplasmic dynein heavy chain: the servant of many masters

“…Mutations in the enzyme glycyl-tRNA synthetase ( GARS ) cause motor and sensory axon loss in humans due to dose-dependent gain of function and give rise to clinical phenotypes that range from forms of CMT neuropathy to severe infantile SMA. A mouse with a missense mutation in the Gars gene that has locomotor and sensory deficits was crossed to Dync1h1 +/Loa mice and, as expected, the double mutants were more severely affected than either parent [67] . However, it is presently unclear whether this increase in severity is linked to a defect in the known role of GARS in translation, amino acid mischarging, or a still unknown mechanism [68] .…”

Aminoacyl‐tRNA synthetases in medicine and disease

“…A mutation in the GARS coding region was associated with CMT disease type 2D and distal spinal muscular atrophy type V. CMT disease comprises a genetically and clinically heterogeneous group of autosomal‐dominant peripheral neuropathies characterized by progressive degeneration of distal motor and sensory neuron function. Additional dominantly inherited missense mutations in GARS have been implicated in CMT disease (Achilli et al, 2009; Banks et al, 2009; Hamaguchi et al, 2010; James et al, 2006; Motley et al, 2010). In this section we focus on mutations in cytoplasmic ARSs associated with CMT disease and their potential underlying mechanisms.…”

VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy

“…An alternative pathogenic mechanism implicating the contribution of VRK1 may be a consequence of its interaction with GARS, 41 a gene whose mutations are also associated with distal neuropathies 63–65 . However, the role of aminoacyl‐tRNA‐synthetases in these diseases is unknown, but may be a consequence of altering neurite formation 66 and peripheral axons 67,68 …”