Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects Bertrand Perroud 1. , Paymaan Jafar-Nejad 2. , William R. Wikoff 1 , Jennifer R. Gatchel 2 , Lu Wang 3 , Dinesh K. Barupal 1 , Juan Crespo-Barreto 2 , Oliver Fiehn 1 , Huda Y. Zoghbi 2,4 * . , Rima Kaddurah-Daouk 5 * . 1 UC Davis Genome Center, University of California Davis, Davis, California, United States of America, 2 Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America, 3 Department of Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America, 4 The Departments of Pediatrics, Neurology, and Neuroscience and the Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America, 5 Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America Abstract 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. Citation: Perroud B, Jafar-Nejad P, Wikoff WR, Gatchel JR, Wang L, et al. (2013) Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects. PLoS ONE 8(8): e70610. doi:10.1371/journal.pone.0070610 Editor: Shi Yu Yang, University College London, United Kingdom Received April 1, 2013; Accepted June 21, 2013; Published August 2, 2013 Copyright: ß 2013 Perroud et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was supported in part by funding from NIH R24 GM078233, and RC2 5RC2GM092729 ‘‘Pharmacometabolomics Research Network’’, both directed by RKD as well as by grant NIH 1U24DK097154 to OF. This work was also in part supported by NINDS grant NS27699 and HHMI to HYZ and NICHD grant HD24064 to BCM-IDDRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: hzoghbi@bcm.tmc.edu (HZ); kaddu001@mc.duke.edu (RKD) . These authors contributed equally to this work. Introduction Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease that is caused by the expansion of a translated CAG repeat in ATAXIN1 (ATXN1). SCA1 is character- ized by progressive loss of balance and coordination, mild cognitive impairments, speaking and swallowing difficulties, and eventually respiratory failure leading to premature death [1]. The toxic effects of the glutamine-expanded protein result in variable degrees of neurodegeneration, predominantly in the cerebellum, brainstem and spinocerebellar tracts [2]. A knock-in mouse model of SCA1 (Sca1 154Q/+ ) recapitulates many aspects of the human disease [3], enabling us to study SCA1 pathophysiology and test therapeutic candidates. Molecular mechanisms that underlie the pathophysiology of SCA1 are slowly becoming understood [4]. The dysregulation of several neuronal genes that has been observed in the tissue of humans with SCA1 has also been found in the Purkinje cells of SCA1 transgenic mice, even at the pre- symptomatic stage [4]. In light of this notion, Watase et al. [5] treated Sca1 154Q/+ mice with lithium—which exerts neuroprotec- tive effects possibly by affecting gene transcription—and demon- strated that lithium rescues several SCA1 phenotypes in this model. Lithium has been the standard pharmacological treatment for bipolar disorder for over fifty years. During the past two decades, attention has been drawn to the neuroprotective properties of lithium against diverse insults, including glutamate-induced excitotoxicity and endoplasmic reticulum stress [6]. Multiple molecular pathways such as phosphoinositides [7,8], protein kinase C signaling pathway [9] and glycogen synthase kinase 3 activity could explain some of the neuroprotective properties of lithium [10–13]. It is unclear how lithium improves the SCA1 disease model and what metabolic changes might be modified. There is no biological marker for following the SCA1 disease course or for measuring the effects of lithium or any other therapy on patients under the PLOS ONE | www.plosone.org 1 August 2013 | Volume 8 | Issue 8 | e70610