Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects.
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.
UC Davis Genome Center, University of California Davis, Davis, California, United States of America.
Bertrand
B
Perroud
Paymaan
P
Jafar-Nejad
William R
WR
Wikoff
Jennifer R
JR
Gatchel
Lu
L
Wang
Dinesh K
DK
Barupal
Juan
J
Crespo-Barreto
Oliver
O
Fiehn
Huda Y
HY
Zoghbi
Rima
R
Kaddurah-Daouk
D000818:Animals; D000950:Antigens, Ly / Q000502:physiology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D000950:Antigens, Ly; D014150:Antipsychotic Agents; D015415:Biomarkers; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D008094:Lithium