Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

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

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1154Q/+). 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 Sca1154Q/+ 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 Sca1154Q/+ mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1154Q/+ cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1154Q/+ 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, Sca1154Q/+ 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 Sca1154Q/+ mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.

Original languageEnglish (US)
Article numbere70610
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 7 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Perroud, B., Jafar-Nejad, P., Wikoff, W. R., Gatchel, J. R., Wang, L., Barupal, D. K., Crespo-Barreto, J., Fiehn, O., Zoghbi, H. Y., & Kaddurah-Daouk, R. (2013). Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects. PLoS One, 8(8), [e70610]. https://doi.org/10.1371/journal.pone.0070610