Publication
Title
Metabolite profile of a mouse model of Charcot-Marie-Tooth type 2D neuropathy : implications for disease mechanisms and interventions
Author
Abstract
Charcot-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.
Language
English
Source (journal)
Biology Open (BiO)
Publication
2016
ISSN
2046-6390
Volume/pages
5:7(2016), p. 908-920
ISI
000380569100004
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
[E?say:metaLocaldata.cgzprojectinf]
Unraveling the molecular architecture of peripheral nerves- a system genetics approach.
Unraveling the nuclear function of tyrosyl-tRNA synthetase and its connection to Dominant Intermediate Charcot-Marie -Tooth type C disease.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 02.09.2016
Last edited 20.11.2017
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