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DOI: 10.1055/s-0031-1271701
© Georg Thieme Verlag KG Stuttgart · New York
Proteome-Based Pathway Modelling of Psychiatric Disorders
Publikationsverlauf
Publikationsdatum:
04. Mai 2011 (online)
![](https://www.thieme-connect.de/media/pharmaco/2011S01/lookinside/thumbnails/10.1055-s-0031-1271701-1.jpg)
Abstract
The etiopathogenesis of many psychiatric illnesses remains unclear and a variety of these diseases can coexist, partly mimicking each other while contributing to and distorting symptomatic expressions. To understand the processes involved, it is necessary to unravel signalling pathways, complex interaction networks and metabolic alterations involving a plethora of anatomical components. When addressing such largely obscure mechanisms, primary data mainly based on genomics and differential gene expression patterns turns out to be of limited usefulness. Numerous direct as well as very indirect processes modulate and dissociate gene expression from protein functions and physiological effects. Proteomics approaches that utilise metabolic labelling and high-throughput mass spectrometry to provide proteome dynamics data need to be utilised. However, the data thus gathered encompasses a complex assembly of numerous types of intermixed cells, representing biological processes that occur in both time and space across several scalar levels. The complexities represented are such that to analytically approach these diseases, a systems standpoint becomes necessary. This implies multiple experimental interrogations in an iterative interplay between experimentation and modelling. While this may be reasonably considered in the context of in vitro systems, it can hardly be contemplated when addressing CNS tissues from heterogeneous human origins, thereby imposing serious constraints upon the investigation of human cognitive disorders. In this article, the authors expose a paradigm that addresses and alleviates at least some of these major difficulties. Based on the reasoned utilisation of trait animal models and human material, this approach has already started to deliver novel and directly exploitable knowledge.
References
- 1 Arguello PA, Markx S, Gogos JA. et al . Development of animal models for schizophrenia. Dis Model Mech. 2010; 3 22-26
- 2 Beasley CL, Pennington K, Behan A. et al . Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: Evidence for disease-associated changes. Proteomics. 2006; 6 3414-3425
- 3 Ben Achour S, Pascual O. Glia: The many ways to modulate synaptic plasticity. Neurochem Int. 2010;
- 4 Bergemann ER, Boles RG. Maternal inheritance in recurrent early-onset depression. Psychiatr Genet. 2010; 20 31-34
- 5 Berretta S, Benes FM. A rat model for neural circuitry abnormalities in schizophrenia. Nat Protoc. 2006; 1 833-839
- 6 Bienvenu OJ, Davydow DS, Kendler KS. Psychiatric ‘diseases’ versus behavioral disorders and degree of genetic influence. Psychol Med. 2010; 1-8
- 7 Bosler O, Girardet C, Sage-Ciocca D. et al . [Mechanisms of structural plasticity associated with photic synchronization of the circadian clock within the suprachiasmatic nucleus]. J Soc Biol. 2009; 203 49-63
- 8 Bruggeman FJ. Systems biology: from possible to plausible to actual models. FEBS J. 2009; 276 885
- 9 Cedersund G, Roll J. Systems biology: model based evaluation and comparison of potential explanations for given biological data. FEBS J. 2009; 276 903-922
- 10 Choudhuri S. Small noncoding RNAs: biogenesis, function, and emerging significance in toxicology. J Biochem Mol Toxicol. 2010; 24 195-216
- 11 Chvatal A, Anderova M, Kirchhoff F. Three-dimensional confocal morphometry – a new approach for studying dynamic changes in cell morphology in brain slices. J Anat. 2007; 210 671-683
- 12 De Keyser J, Mostert JP, Koch MW. Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci. 2008; 267 3-16
- 13 DeFelipe J, Alonso-Nanclares L, Arellano JI. Microstructure of the neocortex: comparative aspects. J Neurocytol. 2002; 31 299-316
- 14 Defelipe J, Fields RD, Hof PR. et al . Cortical white matter: beyond the pale remarks, main conclusions and discussion. Front Neuroanat. 2010; 4 4
- 15 Eastwood SL, Harrison PJ. Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia. Schizophr Res. 2005; 79 181-188
- 16 England PM. Bridging the gaps between synapses, circuits, and behavior. Chem Biol. 2010; 17 607-615
- 17 Enomoto T, Noda Y, Nabeshima T. Phencyclidine and genetic animal models of schizophrenia developed in relation to the glutamate hypothesis. Methods Find Exp Clin Pharmacol. 2007; 29 291-301
- 18 Fellin T. Communication between neurons and astrocytes: relevance to the modulation of synaptic and network activity. J Neurochem. 2009; 108 533-544
- 19 Filiou MD, Bisle B, Reckow S. et al . Profiling of mouse synaptosome proteome and phosphoproteome by IEF. Electrophoresis. 2010; 31 1294-1301
- 20 Fineberg NA, Saxena S, Zohar J. et al . Obsessive-compulsive disorder: boundary issues. CNS Spectr. 2007; 12 359-364, 367–375
- 21 Gadal F, Bozic C, Pillot-Brochet C. et al . Integrated transcriptome analysis of the cellular mechanisms associated with Ha-ras-dependent malignant transformation of the human breast epithelial MCF7 cell line. Nucleic Acids Res. 2003; 31 5789-5804
- 22 Gadal F, Starzec A, Bozic C. et al . Integrative analysis of gene expression patterns predicts specific modulations of defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells. J Mol Endocrinol. 2005; 34 61-75
- 23 Geier F, Timmer J, Fleck C. Reconstructing gene-regulatory networks from time series, knock-out data, and prior knowledge. BMC Syst Biol. 2007; 1 11
- 24 Girardet C, Blanchard MP, Ferracci G. et al . Daily changes in synaptic innervation of VIP neurons in the rat suprachiasmatic nucleus: contribution of glutamatergic afferents. Eur J Neurosci. 2010; 31 359-370
- 25 Glessner JT, Hakonarson H. Common variants in polygenic schizophrenia. Genome Biol. 2009; 10 236
- 26 Gourion D, Gourevitch R, Leprovost JB. et al . [Neurodevelopmental hypothesis in schizophrenia]. Encephale. 2004; 30 109-118
- 27 Gross G, Huber G. Schizophrenia: neurodevelopmental disorder or degenerative brain process?. Fortschr Neurol Psychiatr. 2008; 76 (S 01) S57-S62
- 28 Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med. 2007; 13 54-63
- 29 Halassa MM, Fellin T, Haydon PG. Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology. 2009; 57 343-346
- 30 Halassa MM, Fellin T, Takano H. et al . Synaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007; 27 6473-6477
- 31 Hambsch B, Chen BG, Brenndorfer J. et al . Methylglyoxal-mediated anxiolysis involves increased protein modification and elevated expression of glyoxalase 1 in the brain. J Neurochem. 2010; 113 1240-1251
- 32 Haseloff RF, Blasig IE, Bauer HC. et al . In search of the astrocytic factor(s) modulating blood-brain barrier functions in brain capillary endothelial cells in vitro. Cell Mol Neurobiol. 2005; 25 25-39
- 33 Hauber W. Dopamine release in the prefrontal cortex and striatum: temporal and behavioural aspects. Pharmacopsychiatry. 2010; 43 (S 01) S32-S41
- 34 Iris F, Gea M, Lampe PH. et al . [Production and implementation of predictive biological models]. Med Sci (Paris). 2009; 25 608-616
- 35 Karl T, Chesworth R, Duffy L. et al . Acoustic startle response and sensorimotor gating in a genetic mouse model for the Y1 receptor. Neuropeptides. 2010; 44 233-239
- 36 Koenig JI, Elmer GI, Shepard PD. et al . Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia. Behav Brain Res. 2005; 156 251-261
- 37 Kohl P, Crampin EJ, Quinn TA. et al . Systems biology: an approach. Clin Pharmacol Ther. 2010; 88 25-33
- 38 Korolainen MA, Nyman TA, Aittokallio T. et al . An update on clinical proteomics in Alzheimer's research. J Neurochem. 2010; 112 1386-1414
- 39 Koval M. Pathways and control of connexin oligomerization. Trends Cell Biol. 2006; 16 159-166
- 40 Lee PR, Brady DL, Shapiro RA. et al . Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin. Brain Res. 2007; 1156 152-167
- 41 Lee Y, Gaskins D, Anand A. et al . Glia mechanisms in mood regulation: a novel model of mood disorders. Psychopharmacology (Berl). 2007; 191 55-65
- 42 Lehotzky A, Lau P, Tokesi N. et al . Tubulin polymerization-promoting protein (TPPP/p25) is critical for oligodendrocyte differentiation. Glia. 2010; 58 157-168
- 43 Liebal UW, Millat T, de Jong IG. et al . How mathematical modelling elucidates signalling in B. subtilis. Mol Microbiol. 2010;
- 44 Liljenstrom H. Network effects of synaptic modifications. Pharmacopsychiatry. 2010; 43 (S 01) S67-S81
- 45 Lipska BK. Using animal models to test a neurodevelopmental hypothesis of schizophrenia. J Psychiatry Neurosci. 2004; 29 282-286
- 46 Maccarrone G, Turck CW, Martins-de-Souza D. Shotgun mass spectrometry workflow combining IEF and LC-MALDI-TOF/TOF. Protein J. 2010; 29 99-102
- 47 Martins-De-Souza D, Dias-Neto E, Schmitt A. et al . Proteome analysis of schizophrenia brain tissue. World J Biol Psychiatry. 2010; 11 110-120
- 48 Martins-de-Souza D, Harris LW, Guest PC. et al . The role of proteomics in depression research. Eur Arch Psychiatry Clin Neurosci. 2009;
- 49 Martins-de-Souza D, Maccarrone G, Wobrock T. et al . Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia. J Psychiatr Res. 2010;
- 50 McNally L, Bhagwagar Z, Hannestad J. Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr. 2008; 13 501-510
- 51 Menolascina F, Bellomo D, Maiwald T. et al . Developing optimal input design strategies in cancer systems biology with applications to microfluidic device engineering. BMC Bioinformatics. 2009; 10 (S 12) S4
- 52 Meyer U, Feldon J. Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol. 2010; 90 285-326
- 53 Meyer U, Feldon J, Fatemi SH. In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev. 2009; 33 1061-1079
- 54 Mitterauer BJ. The syncytiopathy hypothesis of depression: downregulation of glial connexins may protract synaptic information processing and cause memory impairment. Med Hypotheses. 2010; 74 497-502
- 55 Moore MN, Noble D. Editorial: computational modelling of cell & tissue processes & function. J Mol Histol. 2004; 35 655-658
- 56 Na ES, Monteggia LM. The role of MeCP2 in CNS development and function. Horm Behav. 2010;
- 57 Ng MY, Levinson DF, Faraone SV. et al . Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol Psychiatry. 2009; 14 774-785
- 58 Niculescu AB. Genomic studies of mood disorders – the brain as a muscle?. Genome Biol. 2005; 6 215
- 59 Noda Y, Mouri A, Waki Y. et al . [Development of animal models for schizophrenia based on clinical evidence: expectation for psychiatrists]. Nihon Shinkei Seishin Yakurigaku Zasshi. 2009; 29 47-53
- 60 Oberheim NA, Takano T, Han X. et al . Uniquely hominid features of adult human astrocytes. J Neurosci. 2009; 29 3276-3287
- 61 Peters BD, Blaas J, de Haan L. Diffusion tensor imaging in the early phase of schizophrenia: What have we learned?. J Psychiatr Res. 2010;
- 62 Pietraszek M, Michaluk J, Romanska I. et al . 1-Methyl-1,2,3,4-tetrahydroisoquinoline antagonizes a rise in brain dopamine metabolism, glutamate release in frontal cortex and locomotor hyperactivity produced by MK-801 but not the disruptions of prepulse inhibition, and impairment of working memory in rat. Neurotox Res. 2009; 16 390-407
- 63 Pouillot F, Blois H, Iris F. Genetically engineered virulent phage banks in the detection and control of emergent pathogenic bacteria. Biosecur Bioterror. 2010; 8 155-169
- 64 Purcell SM, Wray NR, Stone JL. et al . Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009; 460 748-752
- 65 Radyushkin K, El-Kordi A, Boretius S. et al . Complexin2 null mutation requires a ‘second hit’ for induction of phenotypic changes relevant to schizophrenia. Genes Brain Behav. 2010;
- 66 Riley AW, Valdez CR, Barrueco S. et al . Development of a family-based program to reduce risk and promote resilience among families affected by maternal depression: theoretical basis and program description. Clin Child Fam Psychol Rev. 2008; 11 12-29
- 67 Schipke CG, Heuser I, Peters O. Antidepressants act on glial cells: SSRIs and serotonin elicit astrocyte calcium signaling in the mouse prefrontal cortex. J Psychiatr Res. 2010;
- 68 Schroeter ML, Abdul-Khaliq H, Sacher J. et al . Mood disorders are glial disorders: evidence from in vivo studies. Cardiovasc Psychiatry Neurol. 2010; 2010 780645
- 69 Schulze TG. Genetic research into bipolar disorder: the need for a research framework that integrates sophisticated molecular biology and clinically informed phenotype characterization. Psychiatr Clin North Am. 2010; 33 67-82
- 70 Silver RA. Neuronal arithmetic. Nat Rev Neurosci. 2010; 11 474-489
- 71 Suarez-Sola ML, Gonzalez-Delgado FJ, Pueyo-Morlans M. et al . Neurons in the white matter of the adult human neocortex. Front Neuroanat. 2009; 3 7
- 72 Sun J, Jia P, Fanous AH. et al . Schizophrenia gene networks and pathways and their applications for novel candidate gene selection. PLoS One. 2010; 5 e11351
- 73 Sweet RA, Fish KN, Lewis DA. Mapping Synaptic Pathology within Cerebral Cortical Circuits in Subjects with Schizophrenia. Front Hum Neurosci. 2010; 4 44
- 74 Taft RJ, Pang KC, Mercer TR. et al . Non-coding RNAs: regulators of disease. J Pathol. 2010; 220 126-139
- 75 Verkhratsky A. Physiology of neuronal-glial networking. Neurochem Int. 2010;
- 76 Walter M, Henning A, Grimm S. et al . The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiatry. 2009; 66 478-486
- 77 Wang L, Simpson HB, Dulawa SC. Assessing the validity of current mouse genetic models of obsessive-compulsive disorder. Behav Pharmacol. 2009; 20 119-133
- 78 Wang PI, Marcotte EM. It's the machine that matters: Predicting gene function and phenotype from protein networks. J Proteomics. 2010;
- 79 White T, Nelson M, Lim KO. Diffusion tensor imaging in psychiatric disorders. Top Magn Reson Imaging. 2008; 19 97-109
- 80 Williams LE, Light GA, Braff DL. et al . Reduced multisensory integration in patients with schizophrenia on a target detection task. Neuropsychologia. 2010;
- 81 Wilson C, Terry Jr AV. Neurodevelopmental animal models of schizophrenia: role in novel drug discovery and development. Clin Schizophr Relat Psychoses. 2010; 4 124-137
- 82 Wray NR, Visscher PM. Narrowing the boundaries of the genetic architecture of schizophrenia. Schizophr Bull. 2010; 36 14-23
- 83 Young JI, Hong EP, Castle JC. et al . Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci USA. 2005; 102 17551-17558
Correspondence
Dr. C. W. Turck
Proteomics and Biomarkers
Max Planck Institute of
Psychiatry
Kraepelinstraße 2-10
80804 Munich
Germany
Telefon: +49/89/306 223 17
Fax: +49/89/306 226 10
eMail: turck@mpipsykl.mpg.de