Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1(G93A) motor neuron degener

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PLoS One. 2009 Jul 13;4(7):e6218.

Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1(G93A) motor neuron

degeneration phenotype but has little affect on Loa dynein heavy chain mutant

mice.

Banks GT, Bros-Facer V, HP, Chia R, Achilli F, Bryson JB, Greensmith L,

Fisher EM.

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

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.

COONCLUSION/SIGNIFICANCE: These findings raise intriguing possibilities for the

study of pathogenetic mechanisms in all three mouse mutant strains.