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

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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

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Spinocerebellar Ataxias
lithium
Ataxia
Lithium
animal models
purines
mice
cerebellum
Metabolites
Cerebellum
metabolites
neuroprotective effect
Purines
Metabolomics
metabolomics
Sulfur Amino Acids
Plasmas
Oxidative stress
Citric Acid Cycle
Metabolome

ASJC Scopus subject areas

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

Cite this

Perroud, B., Jafar-Nejad, P., Wikoff, W. R., Gatchel, J. R., Wang, L., Barupal, D. K., ... 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

Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects. / 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.

In: PLoS One, Vol. 8, No. 8, e70610, 07.08.2013.

Research output: Contribution to journalArticle

Perroud, B, Jafar-Nejad, P, Wikoff, WR, Gatchel, JR, Wang, L, Barupal, DK, Crespo-Barreto, J, Fiehn, O, Zoghbi, HY & Kaddurah-Daouk, R 2013, 'Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects', PLoS One, vol. 8, no. 8, e70610. https://doi.org/10.1371/journal.pone.0070610
Perroud B, Jafar-Nejad P, Wikoff WR, Gatchel JR, Wang L, Barupal DK et al. Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects. PLoS One. 2013 Aug 7;8(8). e70610. https://doi.org/10.1371/journal.pone.0070610
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. / Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects. In: PLoS One. 2013 ; Vol. 8, No. 8.
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