The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

BMC Research Notes

Paul C Guest¹  Sabine Bahn²  Hassan Rahmoune¹  Bob Amess¹  Pieter J Peeters³  Ilse Lenaerts³  Nancy Aerts³  Laura W Harris¹  Agnes Ernst¹  Murtada Alsaif¹  Daniel Martins-de-Souza¹ 

[1] Dept of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QT, UK;Dept of Neuroscience, Erasmus Medical Centre, Rotterdam, The Netherlands;Janssen Research & Development, Division of Janssen Pharmaceutica N.V, Beerse, Belgium

关键词: Selective reaction monitoring;    Multiple reaction monitoring;    Glycolysis;    Assay;    Preclinical;    Proteomics;    Schizophrenia;    Multiplex;    MRM;    SRM;   

Others  :  1166583
DOI  :  10.1186/1756-0500-5-146

 received in 2011-12-17, accepted in 2012-03-15,  发布年份 2012

【 摘 要 】

Background

Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers.

Methods

We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1), aldolase C (Aldoc), triosephosphate isomerase (Tpi1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), phosphoglycerate mutase 1 (Pgam1), phosphoglycerate kinase 1 (Pgk1) and enolase 2 (Eno2). The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats.

Results

Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls.

Conclusions

This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.

【 授权许可】

   
2012 Martins-de-Souza et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Freedman R: Schizophrenia. N Engl J Med 2003, 349(18):1738-1749.
• [2]Young JW, Zhou X, Geyer MA: Animal models of schizophrenia. Curr Top Behav Neurosci 2010, 4:391-433.
• [3]Kantrowitz JT, Javitt DC: Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clin Schizophr Relat Psychoses 2010, 4(3):189-200.
• [4]Gao XM, Shirakawa O, Du F, Tamminga CA: Delayed regional metabolic actions of phencyclidine. Eur J Pharmacol 1993, 241(1):7-15.
• [5]Iltis I, Koski DM, Eberly LE, Nelson CD, Deelchand DK, Valette J, Ugurbil K, Lim KO, Henry PG: Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized (1)H MRS study. NMR Biomed 2009, 22(7):737-744.
• [6]Vyas NS, Patel NH, Nijran KS, Al-Nahhas A, Puri BK: The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia. Expert Rev Neurother 2011, 11(1):37-51.
• [7]Horvath S, Janka Z, Mirnics K: Analyzing schizophrenia by DNA microarrays. Biol Psychiatry 2011, 69(2):157-162.
• [8]Martins De-Souza D, Dias-Neto E: RNA Biomarkers in Schizophrenia. In Biomarkers for Psychiatric Disorders. 1st edition. Turck CW: Springer; 2009:97-127.
• [9]Martins-De-Souza D, Dias-Neto E, Schmitt A, Falkai P, Gormanns P, Maccarrone G, Turck CW, Gattaz WF: Proteome analysis of schizophrenia brain tissue. World J Biol Psychiatry 2010, 11(2):110-120.
• [10]English JA, Pennington K, Dunn MJ, Cotter DR: The neuroproteomics of schizophrenia. Biol Psychiatry 2011, 69(2):163-172.
• [11]Martins-de-Souza D, Harris LW, Guest PC, Bahn S: The role of energy metabolism dysfunction and oxidative stress in schizophrenia revealed by proteomics. Antioxid Redox Signal 2011, 15(7):2067-2079.
• [12]Kanehisa M, Goto S: KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000, 28(1):27-30.
• [13]Andreasen NC, Arndt S, Swayze V, Cizadlo T, Flaum M, O'Leary D, Ehrhardt JC, Yuh WT: Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 1994, 266(5183):294-298.
• [14]Fucetola R, Newcomer JW, Craft S, Melson AK: Age- and dose-dependent glucose-induced increases in memory and attention in schizophrenia. Psychiatry Res 1999, 88(1):1-13.
• [15]Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN, Carpenter WT: Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry 1992, 49(7):522-530.
• [16]Rezin GT, Amboni G, Zugno AI, Quevedo J, Streck EL: Mitochondrial dysfunction and psychiatric disorders. Neurochem Res 2009, 34(6):1021-1029.
• [17]Martins-de-Souza D, Guest PC, Harris LW, Vanattou-Saifoudine N, Webster MJ, Rahmoune H, Bahn S: Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients. Transl Psychiatry 2012, 2:e87.
• [18]Mann M: Can proteomics retire the western blot? J Proteome Res 2008, 7(8):3065.
• [19]Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, et al.: Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 2004, 9(7):684-697. 643.
• [20]Martins-de-Souza D, Gattaz WF, Schmitt A, Maccarrone G, Hunyadi-Gulyas E, Eberlin MN, Souza GH, Marangoni S, Novello JC, Turck CW, et al.: Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia. J Psychiatr Res 2009, 43(11):978-986.
• [21]Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH: Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 2000, 5(2):142-149.
• [22]Cloninger CR: The discovery of susceptibility genes for mental disorders. Proc Natl Acad Sci USA 2002, 99(21):13365-13367.
• [23]van Os J, Rutten BP, Poulton R: Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull 2008, 34(6):1066-1082.
• [24]Collier DA: Schizophrenia: the polygene princess and the pea. Psychol Med 2008, 38(12):1687-1691. discussion 1818-1620
• [25]Marson B: ''Critical Path'' is on the road forward; FDA reports industry activity is high. The Pink Sheet 2007, 69:29.
• [26]Owens J: Funding for accelerating drug development initiative critical. Nat Rev Drug Discov 2006, 5(4):271.
• [27]Plymoth A, Hainaut P: Proteomics beyond proteomics: toward clinical applications. Curr Opin Oncol 2011, 23(1):77-82.
• [28]Wiesner L, Govender K, Meredith SA, Norman J, Smith PJ: A liquid-liquid LC/MS/MS assay for the determination of artemether and DHA in malaria patient samples. J Pharm Biomed Anal 2011, 55(2):373-378.
• [29]Agger SA, Marney LC, Hoofnagle AN: Simultaneous quantification of apolipoprotein A-I and apolipoprotein B by liquid-chromatography-multiple- reaction-monitoring mass spectrometry. Clin Chem 2010, 56(12):1804-1813.
• [30]Ang CS, Nice EC: Targeted in-gel MRM: a hypothesis driven approach for colorectal cancer biomarker discovery in human feces. J Proteome Res 2010, 9(9):4346-4355.
• [31]Kuster B, Schirle M, Mallick P, Aebersold R: Scoring proteomes with proteotypic peptide probes. Nat Rev Mol Cell Biol 2005, 6(7):577-583.
• [32]Brownridge P, Holman SW, Gaskell SJ, Grant CM, Harman VM, Hubbard SJ, Lanthaler K, Lawless C, O'Cualain R, Sims P, et al.: Global absolute quantification of a proteome: Challenges in the deployment of a QconCAT strategy. Proteomics 2011, 11(15):2957-2970.
• [33]Gnad F, Gunawardena J, Mann M: PHOSIDA 2011: the posttranslational modification database. Nucleic Acids Res 2011, 39:253-260.
• [34]Amann LC, Gandal MJ, Halene TB, Ehrlichman RS, White SL, McCarren HS, Siegel SJ: Mouse behavioral endophenotypes for schizophrenia. Brain Res Bull 2010, 83(3-4):147-161.
• [35]Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Rajagopal L, Harte MK: Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther 2010, 128(3):419-432.
• [36]Kalinichev M, Robbins MJ, Hartfield EM, Maycox PR, Moore SH, Savage KM, Austin NE, Jones DN: Comparison between intraperitoneal and subcutaneous phencyclidine administration in Sprague-Dawley rats: a locomotor activity and gene induction study. Prog Neuropsychopharmacol Biol Psychiatry 2008, 32(2):414-422.
• [37]Martins-de-Souza DE, Menezes-de-Oliveira B, Dos-Santos Farias A, Horiuchi RS, Crepaldi Domingues C, De-Paula E, Marangoni S, Gattaz WF, Dias-Neto E, Camillo Novello J: The use of ASB-14 in combination with CHAPS is the best for solubilization of human brain proteins for two-dimensional gel electrophoresis. Brief Funct Genomic Proteomic 2007, 6(1):70-75.
• [38]MacLean B, Tomazela DM, Shulman N, Chambers M, Finney GL, Frewen B, Kern R, Tabb DL, Liebler DC, MacCoss MJ: Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 2010, 26(7):966-968.
• [39]Schwarz E, Guest PC, Rahmoune H, Harris LW, Wang L, Leweke FM, Rothermundt M, Bogerts B, Koethe D, Kranaster L, et al.: Identification of a biological signature for schizophrenia in serum. Mol Psychiatry 2011, in press. doi:10.1038/mp.2011.42
• [40]Rossinia KVS, Carioua V, Qannaria EM, Fogliatto FS: PLS discriminant analysis applied to conventional sensory profiling data. Food Quality and Preference 2012, 23:18-24.
• [41]Using LC-oa-TOF MSE with a Multivariate Statistical Sample Statistical Sample Profiling Strategy to Distinguish Chinese Red Ginseng from Korean Red Ginseng [http:/ / chromatographyonline.findanalytiche m.com/ lcgc/ article/ articleDetail.jsp?id=632624&sk=&dat e=&pageID=5] webcite