Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia Daniel Martins-de-Souza a, d, * , Giuseppina Maccarrone a , Thomas Wobrock b , Inga Zerr c , Philipp Gormanns a , Stefan Reckow a , Peter Falkai b , Andrea Schmitt b, d , Christoph W. Turck a a Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany b Department of Psychiatry, Von Siebold Str. 5, University of Goettingen, 37075 Goettingen, Germany c Department of Neurology, Robert-Kochstr. 40, University Medical School, Georg-August University Goettingen, 37075 Goettingen, Germany d Laboratório de Neurociências (LIM-27), Inst. Psiquiatria, Fac. de Medicina da Universidade de São Paulo, Rua. Dr. Ovidio Pires de Campos, 785, 05403-010, SP, Brazil article info Article history: Received 9 February 2010 Received in revised form 3 April 2010 Accepted 10 April 2010 Keywords: Schizophrenia Thalamus CSF Proteomics Biomarkers Mass spectrometry abstract Schizophrenia (SCZ) is the result of DNA alterations and environmental factors, which together lead to differential protein expression and ultimately to the development of the illness. The diagnosis is based on clinical symptoms, and the molecular background of SCZ is not completely understood. The thalamus, whose dysfunction has been associated with SCZ based in diverse lines of evidences, plays for instance a pivotal role in the central nervous system as a relay center by re-distributing auditory and visual stimuli from diverse brain regions to the cerebral cortex. We analyzed the proteome of postmortem mediodorsal thalamus (MDT) samples from 11 SCZ patients and 8 non-SCZ individuals by using quantitative shotgun- mass spectrometry and two-dimensional gel electrophoresis. Our analyses identified 551 proteins, 50 of which showed significant differential expression. The main pathways affected by the differentially expressed proteins include energy metabolism, oligodendrocyte metabolism, and cytoskeleton assembly. The potential protein biomarkers candidates myelin basic protein and myelin oligodendrocyte protein were validated by Western blot in the MDT samples and also in cerebrospinal fluid from a separate set of samples of 17 first-episode SCZ patients and 10 healthy controls. The differential expression of m-crys- tallin, protein kinase C-gamma, and glial fibrillary acidic protein were confirmed in MDT. Because we found several glycolysis enzymes to be differentially expressed, we measured the levels of pyruvate and NADPH and found them to be altered in MDT. The protein changes described here corroborate the importance of myelin/oligodendrocyte and energy metabolism in SCZ and highlight new potential biomarkers candidates that may contribute to the understanding of the pathogenesis of this complex disease. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Schizophrenia (SCZ) is a multifactorial, debilitating, psychotic mental disorder that affects about 1% of the population worldwide. It is characterized by a series of negative and positive symptoms that generally occur in young adulthood and, once present, usually persist during the patient’s lifetime (Freedman, 2003). The diag- nosis of SCZ is essentially clinical since no biomarkers have been defined (Frances et al., 1991). Proteome analyses of brain and body fluids from SCZ patients have found disturbances in synapto- genesis, neural plasticity, energy metabolism, and oligodendrocyte metabolism (Martins-de-Souza et al., 2010). Since cellular and molecular arrangements differ between brain regions, it is critical to study the proteome of different areas. The thalamus represents the main part of the diencephalon and plays an indispensable role as a relay center: It organizes stimuli from several brain regions and redistributes them to other parts of the brain, mostly the cerebral cortex. Moreover, it plays pivotal roles in the regulation of different sleep states, wakefulness, and consciousness and is also indirectly involved in the auditory, somatic, visceral, gustatory, and visual sensory systems (Steriade and Llinás, 1988). The thalamus is hypothesized to be a key struc- ture in SCZ since studies in structural and functional magnetic resonance imaging and positron emission tomography (Andreasen et al., 1994; Braus et al., 2002) reported significant alterations in cerebral perfusion and metabolic activity (Min et al., 1999; Talvik et al., 2003). The mediodorsal thalamus (MDT) acts as a central * Corresponding author. Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany. Tel.: þ49 89 30622 630; fax: þ49 89 30622 200. E-mail address: danms90@gmail.com (D. Martins-de-Souza). Contents lists available at ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires 0022-3956/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2010.04.014 Journal of Psychiatric Research 44 (2010) 1176e1189