Abstract
ABSTRACTCharcot–Marie–Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. Charcot–Marie–Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite ‘fingerprint’ we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies.
Highlights
Charcot–Marie–Tooth disease (CMT) comprises a heterogeneous class of hereditary sensory and motor neuropathies caused by genetic defects in as many as 80 different loci in the human genome (Timmerman et al, 2014)
Metabolite profiling of GarsNmf249/+ mice Spinal cords and sciatic nerves were collected from 10 GarsNmf249/+ and 12 wild-type littermate controls at six weeks of age, approximately four weeks after the onset of the mutant phenotype
These samples were used for metabolomics analysis, performed at Metabolon, Inc., in an attempt to identify changes in metabolite abundance that may be indicative of the pathophysiology underlying Charcot– Marie–Tooth type 2D neuropathy (CMT2D)
Summary
Charcot–Marie–Tooth disease (CMT) comprises a heterogeneous class of hereditary sensory and motor neuropathies caused by genetic defects in as many as 80 different loci in the human genome (Timmerman et al, 2014). The mechanism(s) underlying axonal CMTs is much less clear than for the type 1 forms, but several forms of axonal CMT are associated with mutations in tRNA synthetase genes (aminoacyl-tRNA synthetases, or ARSs). These include glycyl-, tyrosyl-, alanyl-, and histidyl-tRNA synthetase (GARS, YARS, AARS and HARS), and more tentatively, methionyl- and lysyl-tRNA synthetase (MARS and KARS) (Antonellis et al, 2003; Jordanova et al, 2006; Latour et al, 2010; McLaughlin et al, 2010; Scheper et al, 2007; Vester et al, 2013)
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