Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium EffectsReport as inadecuate




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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.



Author: Bertrand Perroud , Paymaan Jafar-Nejad , William R. Wikoff, Jennifer R. Gatchel, Lu Wang, Dinesh K. Barupal, Juan Crespo-Barreto,

Source: http://plos.srce.hr/



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