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.
References
[1]
Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23: 217–247.
Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, et al. (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34: 905–919.
[4]
Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, et al. (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452: 713–718.
[5]
Watase K, Gatchel JR, Sun Y, Emanian E, Atkinson R, et al. (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4: e182.
[6]
Chiu CT, Chuang DM (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther 128: 281–304.
Honchar MP, Ackermann KE, Sherman WR (1989) Chronically administered lithium alters neither myo-inositol monophosphatase activity nor phosphoinositide levels in rat brain. J Neurochem 53: 590–594.
[9]
Chen G, Masana MI, Manji HK (2000) Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo. Bipolar Disord 2: 217–236.
[10]
Abe M, Herzog ED, Block GD (2000) Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport 11: 3261–3264.
[11]
Jope RS (2003) Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 24: 441–443.
[12]
Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, et al. (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28: 2576–2588.
[13]
Lee S, Jeong J, Kwak Y, Park SK (2010) Depression research: where are we now? Mol Brain 3: 8.
[14]
Quinones MP, Kaddurah-Daouk R (2009) Metabolomics tools for identifying biomarkers for neuropsychiatric diseases. Neurobiol Dis 35: 165–176.
[15]
Kaddurah-Daouk R, Boyle SH, Matson W, Sharma S, Matson S, et al. (2011) Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept. Translational Psychiatry 1: e26 doi:10.1038/tp.2011.22.
[16]
Kaddurah-Daouk R, Krishnan KR (2009) Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacology 34(1): 173–186 Epub 2008 Oct 8.
[17]
Han X, Rozen S, Boyle SH, Hellegers C, Cheng H, et al. (2011) Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS One 6(7): e21643 Epub 2011 Jul 11.
[18]
Patkar AA, Rozen S, Mannelli P, Matson W, Pae CU, et al. (2009) Alterations in tryptophan and purine metabolism in cocaine addiction: A metabolomic study. Psychopharmacology (Berl) 206(3): 479–489.
[19]
Mannelli P, Patkar A, Rozen S, Matson W, Krishnan , et al. (2009) Opioid use affects antioxidant activity and purine metabolism: Preliminary results. Hum Psychopharmacol 24(8): 666–675.
[20]
Kaddurah-Daouk R, McEvoy J, Baillie RA, Lee D, Yao JK, et al. (2007) Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Mol Psychiatry 12(10): 934–945 Epub 2007 Apr 17.
[21]
Killcoyne S, Carter GW, Smith J, Boyle J (2009) Cytoscape: a community-based framework for network modeling. Methods Mol Biol 563: 219–239.
[22]
Fiehn O, Wohlgemuth G, Scholz M (2005) Setup and annotation of metabolomic experiments by integrating biological and mass spectrometric metadata. Lect Notes Comput Sc 3615: 224–239.
[23]
Scholz M, Fiehn O (2007) SetupX–a public study design database for metabolomic projects. Pac Symp Biocomput 169–180.
[24]
Fiehn O, Wohlgemuth G, Scholz M, Kind T, Lee do Y, et al. (2008) Quality control for plant metabolomics: reporting MSI-compliant studies. Plant J 53: 691–704.
[25]
Rowe MK, Chuang DM (2004) Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6(21): 1–18.
[26]
Basselin M, Chang L, Rapoport SI (2006) Chronic lithium chloride administration to rats elevates glucose metabolism in wide areas of brain, while potentiating negative effects on metabolism of dopamine D2-like receptor stimulation. Psychopharmacology (Berl) 187: 303–311.
[27]
Macko AR, Beneze AN, Teachey MK, Henriksen EJ (2008) Roles of insulin signalling and p38 MAPK in the activation by lithium of glucose transport in insulin-resistant rat skeletal muscle. Arch Physiol Biochem 114: 331–339.
[28]
Shaltiel G, Deutsch J, Rapoport SI, Basselin M, Belmaker RH, et al. (2009) Is phosphoadenosine phosphate phosphatase a target of lithium's therapeutic effect? J Neural Transm 116: 1543–1549.
[29]
Knafo L, Chessex P, Rouleau T, Lavoie JC (2005) Association between hydrogen peroxide-dependent byproducts of ascorbic acid and increased hepatic acetyl-CoA carboxylase activity. Clin Chem 51: 1462–1471.
[30]
Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, et al. (2006) NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols. J Biol Chem 281: 36710–36723.
[31]
Salen G, Polito A (1972) Biosynthesis of 5 -cholestan-3 -ol in cerebrotendinous xanthomatosis. J Clin Invest 51: 134–140.
[32]
Skrede S, Bjorkhem I (1985) A novel route for the biosynthesis of cholestanol, and its significance for the pathogenesis of cerebrotendinous xanthomatosis. Scand J Clin Lab Invest Suppl 177: 15–21.
[33]
Kasama T, Byun DS, Seyama Y (1987) Quantitative analysis of sterols in serum by high-performance liquid chromatography. Application to the biochemical diagnosis of cerebrotendinous xanthomatosis. J Chromatogr 400: 241–246.
[34]
Berridge MJ, Downes CP, Hanley MR (1989) Neural and developmental actions of lithium: a unifying hypothesis. Cell 59: 411–419.
[35]
Cordeiro ML, Gundersen CB, Umbach JA (2003) Dietary lithium induces regional increases of mRNA encoding cysteine string protein in rat brain. J Neurosci Res 73: 865–869.
[36]
Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, et al. (2003) Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol 23: 6027–6036.
[37]
Levin J, Botzel K, Giese A, Vogeser M, Lorenzl S (2010) Elevated levels of methylmalonate and homocysteine in Parkinson's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. Dement Geriatr Cogn Disord 29: 553–559.
[38]
Niklasson F, Agren H, Hallgren R (1983) Purine and monoamine metabolites in cerebrospinal fluid: parallel purinergic and monoaminergic activation in depressive illness? J Neurol Neurosurg Psychiatry 46: 255–260.
[39]
Bourke CA (2012) Motor neurone disease in molybdenum-deficient sheep fed the endogenous purine xanthosine: possible mechanism for Tribulus staggers. Australian Veterinary J 90(7): 272–274.
[40]
Kirkwood JS, Lebold KM, Miranda CL, Wright CL, Miller GW, et al. (2012) Vitamin C deficiency activates the purine nucleotide cycle in zebrafish. J Biol Chem 287: 3833–3841.
[41]
Youdim KA, Martin A, Joseph JA (2000) Essential fatty acids and the brain: possible health implications. Int J Dev Neurosci 18: 383–399.
[42]
Hoyer S, Oesterreich K, Wagner O (1988) Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol 235: 143–148.
[43]
Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, et al. (2004) Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279: 50310–50320.
[44]
Guix FX, Ill-Raga G, Bravo R, Nakaya T, de Fabritiis G, et al. (2009) Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation. Brain 132: 1335–1345.
[45]
Crespo-Barreto J, Fryer JD, Shaw CA, Orr HT, Zoghbi HY (2010) Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet 6: e1001021.
[46]
Lakshmanan J, Seelan RS, Thangavel M, Vadnal RE, Janckila AJ, et al. (2012) Proteomic analysis of rat prefrontal cortex after chronic lithium treatment. J Proteomics Bioinform 5: 140–146.