Journal Article

Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

Zoghbi, Huda Y., Barupal, Dinesh K., Gatchel, Jennifer R., Kaddurah-Daouk, Rima, Fiehn, Oliver, Perroud, Bertrand, Wang, Lu, Wikoff, William R., Crespo-Barreto, Juan, Jafar-Nejad, Paymaan

2013

Overview

We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+)). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1(154Q/+) mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1(154Q/+) cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1(154Q/+) mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1(154Q/+) mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1(154Q/+) mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Analysis / Animals / Annotations / Antigens, Ly - physiology / Antipsychotic Agents - pharmacology / Ascorbic acid / Ataxia / Ataxin / Biology / Biomarkers - metabolism / Biosynthesis / Brain research / Cerebellum / Cerebellum - metabolism / Chemistry / Children & youth / Disease / Disease Models, Animal / Energy metabolism / Fatty acids / Female / Gas chromatography / Gas Chromatography-Mass Spectrometry / Genomes / Genotypes / Hospitals / Kinases / Lipid metabolism / Lipids / Lithium / Lithium - pharmacology / Male / Mass spectrometry / Mass spectroscopy / Mathematics / Medicine / Membrane Proteins - physiology / Metabolic pathways / Metabolism / Metabolites / Metabolome - drug effects / Metabolomics / Mice / Mice, Inbred C57BL / Mice, Knockout / Neurodegeneration / Neuroprotection / Oxidative stress / Pathogenesis / Pharmacology / Proteins / Purines / Rodents / Spinocerebellar ataxia / Sterols / Sulfur / Tricarboxylic acid cycle