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Published in: Journal of Neural Transmission 1/2015

01-08-2015 | Psychiatry and Preclinical Psychiatric Studies - Original Article

Multiplatform metabolome and proteome profiling identifies serum metabolite and protein signatures as prospective biomarkers for schizophrenia

Authors: Khaled Al Awam, Ida Sibylle Haußleiter, Ed Dudley, Rossen Donev, Martin Brüne, Georg Juckel, Johannes Thome

Published in: Journal of Neural Transmission | Special Issue 1/2015

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Abstract

Schizophrenia is a severe mental illness with a biological basis. However, the search for reliable biomarkers suitable for clinical routine has been futile so far. Accordingly, there is a need for innovative approaches such as genomics and proteomics to achieve this goal. In the present study, we compared metabolomic and proteomic data from 26 schizophrenia patients as well as from unaffected controls carefully matched for age and gender in a multi-platform approach. The combined analysis identified many signatures with initially good biomarker characteristics. After statistical analysis and comparison of these identified serum metabolites (analysed by Gas Chromatography Mass Spectrometry) and hydrophobic serum proteins (analysed by matrix-assisted laser desorption ionisation mass spectrometry), several markers (e.g., 2-piperidinec carboxylic acid, 6-deoxy-mannofuranose, galactoseoxime and a serum peptide of m/z 3177) were determined as having the best discriminating value between the groups. Our findings represent a proof of principle indicating that metabolomic and proteomic approaches can be successfully used in psychiatric biomarker research, even though the results should be regarded as preliminary with a need for replication in larger samples.
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Literature
go back to reference Al Awam K, Dudley E, Donev R, Thome J (2012) Protein and peptide profiling as a tool for biomarker discovery in depression. Electrophoresis 33(24):3830–3834CrossRef Al Awam K, Dudley E, Donev R, Thome J (2012) Protein and peptide profiling as a tool for biomarker discovery in depression. Electrophoresis 33(24):3830–3834CrossRef
go back to reference American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (4th ed., textrev.). American Psychiatric Press, Washington, DC American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (4th ed., textrev.). American Psychiatric Press, Washington, DC
go back to reference Berger GE, Smesny S, Amminger GP (2006) Bioactive lipids in schizophrenia. Int Rev Psychiatry 18(2):85–98PubMedCrossRef Berger GE, Smesny S, Amminger GP (2006) Bioactive lipids in schizophrenia. Int Rev Psychiatry 18(2):85–98PubMedCrossRef
go back to reference Bicikova M, Hill M, Ripova D, Mohr P, Hampl R (2013) Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia. J Steroid Biochem Mol Biol 133:77–83PubMedCrossRef Bicikova M, Hill M, Ripova D, Mohr P, Hampl R (2013) Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia. J Steroid Biochem Mol Biol 133:77–83PubMedCrossRef
go back to reference Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRef Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95CrossRef
go back to reference Budczies J, Denkert C, Müller BM, Brockmöller SF, Klauschen F, Györffy B, Dietel M, Richter-Ehrenstein C, Marten U, Salek RM, Griffin JL, Hilvo M, Orešič M, Wohlgemuth G, Fiehn O (2012) Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue—a GC-TOFMS based metabolomics study. BMC Genom 13:334–344CrossRef Budczies J, Denkert C, Müller BM, Brockmöller SF, Klauschen F, Györffy B, Dietel M, Richter-Ehrenstein C, Marten U, Salek RM, Griffin JL, Hilvo M, Orešič M, Wohlgemuth G, Fiehn O (2012) Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue—a GC-TOFMS based metabolomics study. BMC Genom 13:334–344CrossRef
go back to reference Diz AP, Carvajal-Rodríguez A, Skibinski DO (2011) Multiple hypothesis testing in proteomics: a strategy for experimental work. Mol Cell Proteomics 10(3):M110.004374PubMedCentralPubMedCrossRef Diz AP, Carvajal-Rodríguez A, Skibinski DO (2011) Multiple hypothesis testing in proteomics: a strategy for experimental work. Mol Cell Proteomics 10(3):M110.004374PubMedCentralPubMedCrossRef
go back to reference Domenici E, Willé DR, Tozzi F, Prokopenko I, Miller S, McKeown A, Brittain C, Rujescu D, Giegling I, Turck CW, Holsboer F, Bullmore ET, Middleton L, Merlo-Pich E, Alexander RC, Muglia P (2010) Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One 5(2):e9166PubMedCentralPubMedCrossRef Domenici E, Willé DR, Tozzi F, Prokopenko I, Miller S, McKeown A, Brittain C, Rujescu D, Giegling I, Turck CW, Holsboer F, Bullmore ET, Middleton L, Merlo-Pich E, Alexander RC, Muglia P (2010) Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One 5(2):e9166PubMedCentralPubMedCrossRef
go back to reference Dudley E, Hässler F, Thome J (2011) Profiling for novel proteomics biomarkers in neurodevelopmental disorders. Expert Rev Proteomics 8(1):127–136PubMedCrossRef Dudley E, Hässler F, Thome J (2011) Profiling for novel proteomics biomarkers in neurodevelopmental disorders. Expert Rev Proteomics 8(1):127–136PubMedCrossRef
go back to reference Estrada R, Yappert MC (2004) Regional phospholipid analysis of porcine lens membranes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J Mass Spectrom 39(12):1531–1540PubMedCrossRef Estrada R, Yappert MC (2004) Regional phospholipid analysis of porcine lens membranes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J Mass Spectrom 39(12):1531–1540PubMedCrossRef
go back to reference Falkai P, Mike O, Inez MG, Paul H, Andras BG, Sophia F, MEOS Consortium (2008) A roadmap to disentangle the molecular etiology of schizophrenia. Eur Psychiatry 23(4):224–232PubMedCrossRef Falkai P, Mike O, Inez MG, Paul H, Andras BG, Sophia F, MEOS Consortium (2008) A roadmap to disentangle the molecular etiology of schizophrenia. Eur Psychiatry 23(4):224–232PubMedCrossRef
go back to reference Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226(1):497–509PubMed Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226(1):497–509PubMed
go back to reference Gonzalez-Burgos G, Fish KN, Lewis DA (2011) GABA neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia. Neural Plast. 723184 (Epub) Gonzalez-Burgos G, Fish KN, Lewis DA (2011) GABA neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia. Neural Plast. 723184 (Epub)
go back to reference Gutiérrez MC, Delgado-Coello BA (1989) Influence of pipecolic acid on the release and uptake of [3H]GABA from brain slices of mouse cerebral cortex. Neurochem Res 14(5):405–408PubMedCrossRef Gutiérrez MC, Delgado-Coello BA (1989) Influence of pipecolic acid on the release and uptake of [3H]GABA from brain slices of mouse cerebral cortex. Neurochem Res 14(5):405–408PubMedCrossRef
go back to reference He Y, Yu Z, Giegling I, Xie L, Hartmann AM, Prehn C, Adamski J, Kahn R, Li Y, Illig T, Wang-Sattler R, Rujescu D (2012) Schizophrenia shows a unique metabolomics signature in plasma. Transl Psychiatry 2:e149PubMedCentralPubMedCrossRef He Y, Yu Z, Giegling I, Xie L, Hartmann AM, Prehn C, Adamski J, Kahn R, Li Y, Illig T, Wang-Sattler R, Rujescu D (2012) Schizophrenia shows a unique metabolomics signature in plasma. Transl Psychiatry 2:e149PubMedCentralPubMedCrossRef
go back to reference Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D, Gerth CW, Gross S, Schreiber D, Lilley K, Wayland M, Oxley D, Leweke FM, Bahn S (2008) Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues. Mol Psychiatry 13(12):1118–1128PubMedCrossRef Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D, Gerth CW, Gross S, Schreiber D, Lilley K, Wayland M, Oxley D, Leweke FM, Bahn S (2008) Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues. Mol Psychiatry 13(12):1118–1128PubMedCrossRef
go back to reference Jaros JA, Martins-de-Souza D, Rahmoune H, Rothermundt M, Leweke FM, Guest PC, Bahn S (2012) Protein phosphorylation patterns in serum from schizophrenia patients and healthy controls. J Proteomics 5(76):43–55CrossRef Jaros JA, Martins-de-Souza D, Rahmoune H, Rothermundt M, Leweke FM, Guest PC, Bahn S (2012) Protein phosphorylation patterns in serum from schizophrenia patients and healthy controls. J Proteomics 5(76):43–55CrossRef
go back to reference Krakowski M, Czobor P (2011) Cholesterol and cognition in schizophrenia: a double-blind study of patients randomized to clozapine, olanzapine and haloperidol. Schizophr Res 130(1–3):27–33PubMedCrossRef Krakowski M, Czobor P (2011) Cholesterol and cognition in schizophrenia: a double-blind study of patients randomized to clozapine, olanzapine and haloperidol. Schizophr Res 130(1–3):27–33PubMedCrossRef
go back to reference La YJ, Wan CL, Zhu H, Yang YF, Chen YS, Pan YX, Feng GY, He L (2007) Decreased levels of apolipoprotein A-I in plasma of schizophrenic patients. J Neural Transm 114(5):657–663PubMedCrossRef La YJ, Wan CL, Zhu H, Yang YF, Chen YS, Pan YX, Feng GY, He L (2007) Decreased levels of apolipoprotein A-I in plasma of schizophrenic patients. J Neural Transm 114(5):657–663PubMedCrossRef
go back to reference Levin Y, Wang L, Schwarz E, Koethe D, Leweke FM, Bahn S (2010) Global proteomic profiling reveals altered proteomic signature in schizophrenia serum. Mol Psychiatry 15(11):1088–1100PubMedCrossRef Levin Y, Wang L, Schwarz E, Koethe D, Leweke FM, Bahn S (2010) Global proteomic profiling reveals altered proteomic signature in schizophrenia serum. Mol Psychiatry 15(11):1088–1100PubMedCrossRef
go back to reference Martins-De-Souza D, Wobrock T, Zerr I, Schmitt A, Gawinecka J, Schneider-Axmann T, Falkai P, Turck CW (2010) Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 d-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls. World J Biol Psychiatry 11(5):719–728PubMedCrossRef Martins-De-Souza D, Wobrock T, Zerr I, Schmitt A, Gawinecka J, Schneider-Axmann T, Falkai P, Turck CW (2010) Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 d-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls. World J Biol Psychiatry 11(5):719–728PubMedCrossRef
go back to reference Meister L, Alawam K, Dudley E, Taurines R, Müller SE, Walter M, Höppner J, Teipel S, Donev RM, Eckert A, Wiesbeck GA, Thome J (2011) Pilot study of the application of magnetic bead protein profiling to the study of biomarkers in addiction research. World J Biol Psychiatry 12(1):80–84PubMedCrossRef Meister L, Alawam K, Dudley E, Taurines R, Müller SE, Walter M, Höppner J, Teipel S, Donev RM, Eckert A, Wiesbeck GA, Thome J (2011) Pilot study of the application of magnetic bead protein profiling to the study of biomarkers in addiction research. World J Biol Psychiatry 12(1):80–84PubMedCrossRef
go back to reference Nishio H, Giacobini E (1981) Brain uptake of pipecolic acid, amino acids, and amines following intracarotid injection in the mouse. Neurochem Res 6(8):835–845PubMedCrossRef Nishio H, Giacobini E (1981) Brain uptake of pipecolic acid, amino acids, and amines following intracarotid injection in the mouse. Neurochem Res 6(8):835–845PubMedCrossRef
go back to reference Orešič M, Tang J, Seppänen-Laakso T, Mattila I, Saarni SE, Saarni SI, Lönnqvist J, Sysi-Aho M, Hyötyläinen T, Perälä J, Suvisaari J (2011) Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Med 3(3):19PubMedCentralPubMedCrossRef Orešič M, Tang J, Seppänen-Laakso T, Mattila I, Saarni SE, Saarni SI, Lönnqvist J, Sysi-Aho M, Hyötyläinen T, Perälä J, Suvisaari J (2011) Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Med 3(3):19PubMedCentralPubMedCrossRef
go back to reference Orešič M, Seppänen-Laakso T, Sun D, Tang J, Therman S, Viehman R, Mustonen U, van Erp TG, Hyötyläinen T, Thompson P, Toga AW, Huttunen MO, Suvisaari J, Kaprio J, Lönnqvist J, Cannon TD (2012) Phospholipids and insulin resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia. Genome Med 4(1):1PubMedCentralPubMedCrossRef Orešič M, Seppänen-Laakso T, Sun D, Tang J, Therman S, Viehman R, Mustonen U, van Erp TG, Hyötyläinen T, Thompson P, Toga AW, Huttunen MO, Suvisaari J, Kaprio J, Lönnqvist J, Cannon TD (2012) Phospholipids and insulin resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia. Genome Med 4(1):1PubMedCentralPubMedCrossRef
go back to reference Ray P, Manach YL, Riou B, Houle TT (2010) Statistical evaluation of a biomarker. Anesthesiology 112:1023–1040PubMedCrossRef Ray P, Manach YL, Riou B, Houle TT (2010) Statistical evaluation of a biomarker. Anesthesiology 112:1023–1040PubMedCrossRef
go back to reference Roser M, Josic D, Kontou M, Mosetter K, Maurer P, Reutter W (2009) Metabolism of galactose in the brain and liver of rats and its conversion into glutamate and other amino acids. J Neural Trans 116(2):131–139CrossRef Roser M, Josic D, Kontou M, Mosetter K, Maurer P, Reutter W (2009) Metabolism of galactose in the brain and liver of rats and its conversion into glutamate and other amino acids. J Neural Trans 116(2):131–139CrossRef
go back to reference Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA, Holcomb HH, Barker PB (2013) In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 39(5):1096–1104PubMedCentralPubMedCrossRef Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA, Holcomb HH, Barker PB (2013) In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 39(5):1096–1104PubMedCentralPubMedCrossRef
go back to reference Schmidt-Glenewinkel T, Nomura Y, Giacobini E (1977) The conversion of lysine into piperidine, cadaverine, and pipecolic acid in the brain and other organs of the mouse. Neurochem Res 2(6):619–937PubMedCrossRef Schmidt-Glenewinkel T, Nomura Y, Giacobini E (1977) The conversion of lysine into piperidine, cadaverine, and pipecolic acid in the brain and other organs of the mouse. Neurochem Res 2(6):619–937PubMedCrossRef
go back to reference Schwarz E, Whitfield P, Nahnsen S, Wang L, Major H, Leweke FM, Koethe D, Lio P, Bahn S (2011) Alterations of primary fatty acid amides in serum of patients with severe mental illness. Front Biosci 3:308–314CrossRef Schwarz E, Whitfield P, Nahnsen S, Wang L, Major H, Leweke FM, Koethe D, Lio P, Bahn S (2011) Alterations of primary fatty acid amides in serum of patients with severe mental illness. Front Biosci 3:308–314CrossRef
go back to reference Stan AD, Lewis DA (2012) Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies. Curr Pharm Biotechnol 13(8):1557–1562PubMedCentralPubMedCrossRef Stan AD, Lewis DA (2012) Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies. Curr Pharm Biotechnol 13(8):1557–1562PubMedCentralPubMedCrossRef
go back to reference Störber G, Ben-Shachar D, Cardon M, Falkai P, Fonteh AN, Gawlik M, Glenthoj BY, Grünblatt E, Jablensky A, Kim YK, Kornhuber J, McNeil TF, Müller N, Oranje B, Saito T, Saoud M, Schmitt A, Schwartz M, Thome J, Uzbekov M, Durany N, Riederer P (2009) Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers. World J Biol Psychiatry 10(2):127–155CrossRef Störber G, Ben-Shachar D, Cardon M, Falkai P, Fonteh AN, Gawlik M, Glenthoj BY, Grünblatt E, Jablensky A, Kim YK, Kornhuber J, McNeil TF, Müller N, Oranje B, Saito T, Saoud M, Schmitt A, Schwartz M, Thome J, Uzbekov M, Durany N, Riederer P (2009) Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers. World J Biol Psychiatry 10(2):127–155CrossRef
go back to reference Taurines R, Dudley E, Conner AC, Grassl J, Jans T, Guderian F, Mehler-Wex C, Warnke A, Gerlach M, Thome J (2010) Serum protein profiling and proteomics in autistic spectrum disorder using magnetic bead-assisted mass spectrometry. Eur Arch Psychiatry Clin Neurosci 260(3):249–255PubMedCrossRef Taurines R, Dudley E, Conner AC, Grassl J, Jans T, Guderian F, Mehler-Wex C, Warnke A, Gerlach M, Thome J (2010) Serum protein profiling and proteomics in autistic spectrum disorder using magnetic bead-assisted mass spectrometry. Eur Arch Psychiatry Clin Neurosci 260(3):249–255PubMedCrossRef
go back to reference Taurines R, Dudley E, Grassl J, Warnke A, Gerlach M, Coogan AN, Thome J (2011) Proteomic research in psychiatry. J Psychopharmacol 25(2):151–196PubMedCrossRef Taurines R, Dudley E, Grassl J, Warnke A, Gerlach M, Coogan AN, Thome J (2011) Proteomic research in psychiatry. J Psychopharmacol 25(2):151–196PubMedCrossRef
go back to reference Tiss A, Smith C, Menon U, Jacobs I, Timms JF, Cramer R (2010) A well-characterised peak identification list of MALDI MS profile peaks for human blood serum. Proteomics 10(18):3388–3392PubMedCrossRef Tiss A, Smith C, Menon U, Jacobs I, Timms JF, Cramer R (2010) A well-characterised peak identification list of MALDI MS profile peaks for human blood serum. Proteomics 10(18):3388–3392PubMedCrossRef
go back to reference Vila-Rodriguez F, Honer WG, Innis SM, Wellington CL, Beasley CL (2011) ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype. J Psychiatry Neurosci 36(1):47–55PubMedCentralPubMedCrossRef Vila-Rodriguez F, Honer WG, Innis SM, Wellington CL, Beasley CL (2011) ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype. J Psychiatry Neurosci 36(1):47–55PubMedCentralPubMedCrossRef
go back to reference Woods AG, Sokolowska I, Taurines R, Gerlach M, Dudley E, Thome J, Darie CC (2012) Potential biomarkers in psychiatry: focus on the cholesterol system. J Cell Mol Med 16(6):1184–1195PubMedCentralPubMedCrossRef Woods AG, Sokolowska I, Taurines R, Gerlach M, Dudley E, Thome J, Darie CC (2012) Potential biomarkers in psychiatry: focus on the cholesterol system. J Cell Mol Med 16(6):1184–1195PubMedCentralPubMedCrossRef
go back to reference Xuan J, Pan G, Qiu Y, Yang L, Su M, Liu Y, Chen J, Feng G, Fang Y, Jia W, Xing Q, He L (2011) Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action. J Proteome Res 10(12):5433–5443PubMedCrossRef Xuan J, Pan G, Qiu Y, Yang L, Su M, Liu Y, Chen J, Feng G, Fang Y, Jia W, Xing Q, He L (2011) Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action. J Proteome Res 10(12):5433–5443PubMedCrossRef
Metadata
Title
Multiplatform metabolome and proteome profiling identifies serum metabolite and protein signatures as prospective biomarkers for schizophrenia
Authors
Khaled Al Awam
Ida Sibylle Haußleiter
Ed Dudley
Rossen Donev
Martin Brüne
Georg Juckel
Johannes Thome
Publication date
01-08-2015
Publisher
Springer Vienna
Published in
Journal of Neural Transmission / Issue Special Issue 1/2015
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI
https://doi.org/10.1007/s00702-014-1224-0

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