Metabolite profile of a mouse model of Charcot-Marie-Tooth type 2D neuropathy: implications for disease mechanisms and interventions.
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.
The Jackson Laboratory, Bar Harbor, 04609 ME, USA.
Preeti
P
Bais
Metabolon Inc., Durham, 27713 NC, USA.
Kirk
K
Beebe
The Jackson Laboratory, Bar Harbor, 04609 ME, USA Graduate School of Biomedical Science and Engineering, University of Maine, Orono, 04469 ME, USA.
Kathryn H
KH
Morelli
The Jackson Laboratory, Bar Harbor, 04609 ME, USA.
Meagan E
ME
Currie
The Jackson Laboratory, Bar Harbor, 04609 ME, USA.
Sara N
SN
Norberg
The Jackson Laboratory, Bar Harbor, 04609 ME, USA Department of Molecular Medicine, USF Health, University of South Florida, Tampa, 33620 FL, USA.
Alexei V
AV
Evsikov
The Jackson Laboratory, Bar Harbor, 04609 ME, USA.
Kathy E
KE
Miers
The Jackson Laboratory, Bar Harbor, 04609 ME, USA.
Kevin L
KL
Seburn
Department of Neurology, Medical University-Sofia, 1431 Sofia, Bulgaria.
Velina
V
Guergueltcheva
National Genetics Laboratory, Department of Obstetrics and Gynecology, University Hospital of Obstetrics and Gynecology, Medical University-Sofia, 1431 Sofia, Bulgaria.
Ivo
I
Kremensky
Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University-Sofia, 1431 Sofia, Bulgaria.
Albena
A
Jordanova
The Jackson Laboratory, Bar Harbor, 04609 ME, USA.
Carol J
CJ
Bult
The Jackson Laboratory, Bar Harbor, 04609 ME, USA Graduate School of Biomedical Science and Engineering, University of Maine, Orono, 04469 ME, USA robert.burgess@jax.org.
Robert W
http://orcid.org/0000-0002-9229-3407
RW
Burgess
Mass Spectrometry; Metabolomics; Peripheral neuropathy; Sciatic nerve; Spinal cord; tRNA synthetase