Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Perroud, B; Jafar-Nejad, P; Wikoff, WR; Gatchel, JR; Wang, L; Barupal, DK; Crespo-Barreto, J; Fiehn, O; Zoghbi, HY; Kaddurah-Daouk, R

Published Date

  • 2013

Published In

Volume / Issue

  • 8 / 8

Start / End Page

  • e70610 -

PubMed ID

  • 23936457

Pubmed Central ID

  • 23936457

Electronic International Standard Serial Number (EISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0070610

Language

  • eng

Conference Location

  • United States