Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects

• Published in: PloS one Vol. 8; no. 8; p. e70610
• Main Authors: Perroud, Bertrand, Jafar-Nejad, Paymaan, Wikoff, William R, Gatchel, Jennifer R, Wang, Lu, Barupal, Dinesh K, Crespo-Barreto, Juan, Fiehn, Oliver, Zoghbi, Huda Y, Kaddurah-Daouk, Rima
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.08.2013; Public Library of Science (PLoS)
• Subjects: 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; Los Angeles California; California; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0070610

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.