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Proteome and transcriptome analysis suggests oligodendrocyte dysfunction in schizophrenia
Journal of Psychiatric Research 44 (2010) 149–156
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Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires
Review
Proteome and transcriptome analysis suggests oligodendrocyte dysfunction in schizophrenia Daniel Martins-de-Souza * Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, D-80804 Munich, Germany
a r t i c l e
i n f o
Article history: Received 8 April 2009 Received in revised form 23 July 2009 Accepted 24 July 2009
Keywords: Schizophrenia Oligodendrocytes Myelin Proteome Proteomics Transcriptome Neurodegeneration
a b s t r a c t Despite all the efforts regarding the treatment of schizophrenia patients and the growing advances in molecular diagnosis studies, the biochemical basis of this debilitating psychotic mental disorder that affects approximately 1% of the world’s population is still not completely comprehended. Several recent clinical and molecular studies, using transcriptome and proteome analyses (TPA), for example, have described the oligodendrocyte dysfunction as a significant feature of the disease. TPA has been extensively used as a biomarker discovery tool, but a detailed and careful interpretation of the generated data can also provide a picture of the integrated biochemical systems that lead to the disease. This review presents the oligodendrocyte role players in schizophrenia pathogenesis as revealed by transcriptome and proteome studies. The presented data contribute to the composition of a scenario that may lead to a better understanding of schizophrenia pathogenesis. Ó 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8.
Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oligodendrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schizophrenia and oligodendrocytes: previous findings . . . . . . . . . Transcriptome and proteome analysis . . . . . . . . . . . . . . . . . . . . . . . Transcriptome and proteome analysis of brain tissue revealed the Schizophrenia and neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . Protein association analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Schizophrenia Schizophrenia (SCZ) is a debilitating, psychotic mental disorder that affects about 1% of the population worldwide (Freedman, 2003). It is a multifactorial disease, characterized by a series of negative and positive symptoms such as auditory and visual hallucinations, slow and disorganized thoughts, difficulty of understanding, memory deficit, difficulty of integrating feelings and * Tel.: +49 89 30622 630; fax: +49 89 30622 200. E-mail address: [email protected] 0022-3956/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2009.07.007
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149 150 150 150 152 153 153 154 154 154 154 154 155
behavior, paranoid delusions and significant social dysfunction that generally occur in young adulthood and, once present, usually persist for the patient’s lifetime (Sawa and Snyder, 2002). A diagnosis of SCZ is essentially made on the basis of clinical symptoms since it has an undefined molecular basis and there is a general lack of biochemical markers (Frances et al., 1991). SCZ is the result of multifactorial endogenous and exogenous interaction. The genetic components are probably the most important endogenous elements of this network, since DNA alterations, which have already been described in SCZ, may lead to differential gene and protein expression. As consequence, physiological
Shotgun 5 SCZ; 4 controls Martins-de-Souza et al. (2009c) – – Anterior temporal lobe (BA38)
–
1) Katsel et al. (2005) 2) McCullumsmith et al. (2007) Anterior Cingulate Cortex (BA24)
Abbreviations used: qPCR: real-time PCR; 2DE: two-dimensional gel electrophoresis; DIGE: differential in gel electrophoresis. a Katsel et al. (2005) studied regions: parietal (BA7), superior frontal gyrus (BA8), frontal cortex (BA10), occipital (BA17), inferior temporal gyrus (BA20), middle temporal gyrus (BA21), superior temporal gyrus (BA22), posterior cingulate (BA:23/31), anterior cingulate (BA32), parahippocampal gyrus (BA:36/28), insular cortex (BA44), hippocampus, caudate nucleus, caudate putamen.
–
2DE 10 SCZ; 10 controls
– –
Clark et al. (2006) 1) Microarray 2) In situ hybridization
qPCR Aberg et al. (2006a,b) Frontal Cortex (BA8)
1) 16 SCZ; 14 controls 2) 41 SCZ; 34 Controls
Dracheva et al. (2006) I – Cingulate Gyrus (Brodmann area 24/32) II – Hippocampus III – Caudate Nucleus IV – Caudate Putamen
55 SCZ; 55 CTRL
– – – qPCR
Katsel et al. (2005) Several regions a
I – 30 SCZ; 25 Controls II – 24 SCZ; 21 Controls III – 23 SCZ; 20 Controls IV – 24 SCZ; 19 Controls
–
– –
– –
– Microarray
Microarray Aston et al. (2004) Temporal cortex (middle temporal gyrus – BA21)
16 SCZ; 14 controls
Tkachev et al. (2003)
12 SCZ; 14 controls
1) 2DE-DIGE 2) 2DE 1) 54 SCZ; 50 controls 2) 35 SCZ; 35 controls 1) Prabakaran et al. (2004) 2) Pennington et al. (2008) Microarray
Methodology
Prefrontal cortex (BA9)
15 SCZ; 15 controls
1) 9 SCZ; 7 controls 2) 9 SCZ; 7 controls
Subjects Proteome Reference Methodology Subjects
1) Hakak et al. (2001) 2) Katsel et al. (2005) 3) Arion et al. (2007)
Transcriptomics and proteomics are ‘‘young sciences” whose names arose from the terms ‘‘transcriptome” and ‘‘proteome” (Velculescu et al., 1997; Wilkins et al., 1996a,b). These sciences can be defined as ‘‘the study of the total set of expressed transcripts and proteins by a genome, cell, tissue or organism at a given time under a determined condition”. Since nowadays these sciences are more complex and complete and so do more than just
Transcriptome reference
4. Transcriptome and proteome analysis
Dorso-lateral prefrontal cortex (BA46)
Brain imaging studies have demonstrated the dysfunction of oligodendrocytes in SCZ. Using magnetic transfer imaging, Foong et al. (2000), studying the temporal lobe, and Kubicki et al. (2005), studying the frontal lobe, have analyzed white matter integrity and found decreased myelin integrity, as well as decreased axonal membranes. In addition, abnormal distribution and decreased density of oligodendrocytes, apoptotic oligodendrocytes, damaged myelin sheaths and a decreased volume density of mitochondria were observed by electron microscopy studies in frontal regions of SCZ brains (Uranova et al., 2001). Decreased levels of phosphatidylcholine, sphingomyelin and galactocerebroside, which play indispensable roles in oligodendrocyte metabolism, were found in the post-mortem thalamus of patients with SCZ (Schmitt et al., 2004). Epigenetic evidence has also shown the potential role of oligodendrocytes in SCZ. Iwamoto et al. (2005) found hypermethylation of gene SOX10, which can lead to an overexpression of structural myelin proteins (Chan et al., 2003) in SCZ patients. Moreover, Liu et al. (2005) described the positive association of the myelin oligodendrocyte glycoprotein (MOG) gene with SCZ in the Chinese Han population, although Zai et al. (2005) did not find the same association in a group of SCZ patients composed by 95% Caucasian subjects. MOG had been previously associated with white matter abnormalities in SCZ, and has a role in the complement cascade (Davis et al., 2003 for review; Hof et al., 2003). Karoutzou et al. (2008) has presented a detailed review of linkage studies and susceptible genes oligodendrocyte-related in SCZ as well as oligodendrocyte-related genes that have already been associated with SCZ.
Table 1 Analysis of gene and proteome expression of post-mortem SCZ brain tissue which have suggested oligodendrocytes dysfunctions.
3. Schizophrenia and oligodendrocytes: previous findings
1) Martins-de-Souza et al. (2009b) 2) Martins-de-Souza et al. (2009a)
Oligodendrocytes are a type of neuroglia constituting approximately 51% of the cells around the soma of large neurons in the human cortex (Polak et al., 1982); their main function is to insulate the axons in the central nervous system (CNS), wrapping it with myelin, providing an electrically-insulating phospholipid layer that facilitate axonal signal by increasing the speed at which the electrical impulses are propagated and by preventing the electrical current from leaving the axon. Trophic signaling among neurons, growth factor synthesis, neuronal survival and development and neurotransmission are other oligodendrocyte functions (Du and Dreyfus, 2002; Deng and Poretz, 2003). A disturbance in the myelin sheath could lead to ion leakage with reduced nerve impulse propagation, consequently compromising neuronal and glial functions. Convergent data from different research fields have described the dysfunction of oligodendrocytes as an important feature in SCZ pathogenesis because of their implication in brain connectivity. Recently, dysfunctions of oligodendrocyte metabolism have been often observed and suggested in SCZ studies of brain tissue (Segal et al., 2007 for review).
1) Microarray 2) Microarray 3) Microarray
2. Oligodendrocytes
1) 12 SCZ; 12 controls 2) 16 SCZ; 14 controls 3) 12 SCZ; 12 controls
imbalances are driven that, combined with environmental factors, trigger the disease. Despite all the clinical and molecular efforts to understand SCZ, some features remain undiscovered.
1) 2DE 2) Shotgun
D. Martins-de-Souza / Journal of Psychiatric Research 44 (2010) 149–156
Brain region
150
151
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identify a complete set of differentially expressed proteins and genes, from now on in this article, transcriptome and proteome analyses (TPA) will be defined as a tool for identifying differentially expressed genes and proteins in pathological states. Most of the transcriptome analyses performed on the brain tissue of SCZ patients have been conducted using cDNA microarray analysis, one of the most powerful tools for large-scale gene expression investigation in human diseases. Some advantages of microarray analysis are that it allows large-scale automated evaluation of thousands of transcripts, requires relatively small amounts of RNA and has low bioinformatics requirements. However, some drawbacks are observed such as only the transcripts present in the array are evaluated (which means unknown genes are not analyzed), complex statistical analysis, high false positive rate and difficulty to perform multiple comparisons. In SCZ transcriptome analysis, real-time PCR (qPCR), Northern blots and in situ hybridization have been used as validation methods.
Most of the proteome analyses of brain tissue of SCZ patients were performed using a combination of two-dimensional gel electrophoresis (2DE) to separate the proteins and mass spectrometry to identify the differentially expressed proteins. The combination of 2DE and mass spectrometry allows the separation of thousands of proteins in a single experiment, a direct software-based comparison of 2DE gels from different samples (i.e. controls versus disease samples) and the unambiguous identification of the proteins. However, it is known that there is a bias towards the highly expressed proteins in 2DE profiles. In addiction, it is difficulty to detect in 2DE profiles extremely acid and extremely basic proteins as well as proteins with very high and very low molecular weights. Shotgun proteomics, which enriches the low-expressed proteins in a high throughput way, has also been used to study brain tissue in SCZ. Western blot, ELISA and antibody arrays have been performed to validate the proteomics findings.
Table 2 Oligodendrocyte-related genes and proteins with altered expression in SCZ brain tissues. Protein name
Gene
Transcriptome alteration
Proteome alteration
Transferrin
TF
Hakak et al. (2001) Tkachev et al. (2003) Katsel et al. (2005) Aberg et al. (2006b) McCullumsmith et al. (2007) Arion et al. (2007)
Prabakaran et al. (2004) Clark et al. (2006) Pennington et al. (2008) Martins-de-Souza et al. (2009b)
20 ,30 -Cyclic nucleotide 30 -phosphodiesterase
CNP
Hakak et al. (2001) Tkachev et al. (2003) Aston et al. (2004) Katsel et al. (2005) Dracheva et al. (2006) McCullumsmith et al. (2007)
Flynn et al. (2003) Prabakaran et al. (2004) Martins-de-Souza et al. (2009a) Martins-de-Souza et al. (2009c)
Myelin basic protein
MBP
Tkachev et al. (2003) Sugai et al. (2004)
Chambers and Perrone-Bizzozero (2004) Martins-de-Souza et al. (2009b) Martins-de-Souza et al. (2009c)
Myelin oligodendrocyte glycoprotein
MOG
Tkachev et al. (2003) Katsel et al. (2005) Arion et al. (2007)
Martins-de-Souza et al. (2009a) Martins-de-Souza et al. (2009c)
Gelsolin
GSN
Hakak et al. (2001) Katsel et al. (2005)
Prabakaran et al. (2004)
Myelin-associated glycoprotein
MAG
Hakak et al. (2001) Tkachev et al. (2003) Aston et al. (2004) Katsel et al. (2005) Aberg et al. (2006b) Dracheva et al. (2006)
–
V-erb-b2 erythroblastic leukemia viral oncogene
ERBB3
McCullumsmith et al. (2007) Hakak et al. (2001) Tkachev et al. (2003) Aston et al. (2004) Katsel et al. (2005)
–
T-Lymphocyte maturation-associated protein
MAL
Hakak et al. (2001) Aston et al. (2004) Sugai et al. (2004) Katsel et al. (2005)
–
Claudin 11; Oligodendrocyte specific protein
CLDN11
Tkachev et al. (2003) Katsel et al. (2005) Dracheva et al. (2006) Weidenhofer et al. (2006)
–
Proteolipid protein
PLP
Tkachev et al. (2003) Aston et al. (2004) Aberg et al. (2006b)
–
Plasmolipin or transmembrane 4 superfamily 11
PLLP/TM4SF11
Aston et al. (2004) Katsel et al. (2005)
–
Quaking homolog
QKI
Aberg et al. (2006a) McCullumsmith et al. (2007) Haroutunian et al. (2006)
–
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TPA of brain tissue in SCZ patients has consistently revealed the differential expression of different classes of genes and proteins, such as those related to oligodendrocytes.
5. Transcriptome and proteome analysis of brain tissue revealed the oligodendrocyte players in schizophrenia TPA has been extensively used to reveal potential SCZ biomarkers in human samples. However, TPA findings can be used not only to reveal biomarkers, but also to identify the players in SCZ pathogenesis, which could lead to better comprehension and elucidation of the disease mechanisms. Consequently, new doors to new research directions will be opening, leading to more specific goals. TPA of brain tissue has revealed potential oligodendrocyte dysfunction in SCZ as well as in other psychiatric disorders, such as major depression (Aston et al., 2005). Studies of neurodevelopment and synaptic circuits in several brain regions from SCZ patients have also found the dysfunction of oligodendrocytes in SCZ (Honer et al., 1999; Flynn et al., 2003; Beasley et al., 2009). Oligodendrocyte dysfunction in SCZ discovered by transcriptome studies in post-mortem tissue was first presented by Hakak et al. (2001) studying the gray matter of the dorsolateral prefrontal cortex (DLPFC), Brodmann’s Area (BA) 46 from 12 SCZ patients and 12 controls (CTRL) as shown in Table 2. Afterwards, subsequent transcriptome analyses corroborated with these findings in the gray and white matter of the prefrontal cortex (BA9) from 15 SCZ patients and 15 CTRL subjects (Tkachev et al., 2003), in the gray and white matter of the middle temporal gyrus (BA21) from 12 SCZ subjects and 14 matched CTRL (Aston et al., 2004) and in the gray and white matter of the DLPFC (BA46) from 12 SCZ subjects and 12 CTRL subjects (Arion et al., 2007). Microarray experiments in multiple cortical and non-cortical regions (Katsel et al., 2005) and validation experiments using real-time PCR and in situ hybridization have been performed in the gray and white matter of multiple samples from the brain regions described in Table 1 (Aberg et al., 2006a,b; Dracheva et al., 2006; McCullumsmith et al., 2007) and the dysfunction in oligodendrocytes metabolism have also been found. The first proteome report concerning oligodendrocyte dysfunction in SCZ was published by Prabakaran et al. (2004) studying gray and white matter of the DLPFC (BA9) from 54 SCZ and 50 CTRL. Subsequent proteome experiments (Table 1) were able to corroborate previous data and even present new oligodendrocyte candidates (Table 2). All the reports described above did not differentiated oligodendrocytes from gray and white matter. All the transcriptome reports shown here (Table 1) have found differential regulation of the myelin-associated glycoprotein (MAG), an indispensable membrane protein in the myelination process and post-natal neural development. However, no proteome reports found differential expression of MAG, which has an isoelectric point (pI) of 4.97 and a molecular weight (MW) of 69,068.52 (theoretical data), so that it should be easily identifiable using available proteomics methods. This suggests that a transcriptional regulation event could change the mRNA concentration of this gene that could be a potential mRNA biomarker. 20 ,30 -cyclic nucleotide 30 -phosphodiesterase (CNP) was found differentially expressed in six transcriptome analyses and three proteome analyses of SCZ brain tissue. CNP is a membrane-bound microtubule-associated protein which links tubulin to cellular membranes regulating the microtubule distribution in the cytoplasm (Bifulco et al., 2002). CNP is a well-characterized marker of myelin-forming cells and in oligodendrocytes interacts with tubulin promoting microtubule assembly for process outgrowth (Lee et al., 2005). Moreover, CNP plays an indispensable role not only in oligodendrocytes but also in axonogenesis (Higuchi et al.,
2005; Kursula, 2008), in cyclic nucleotide catabolic process (Drummond et al., 1962), RNA metabolic process (Boccaccio and Colman, 1995), microtubule cytoskeleton organization and synaptic transmission (Sprinkle et al., 1992; Monoh et al., 1993). Genetic association studies have confirmed the potential CNP role in SCZ pathogenesis (Peirce et al., 2006; Georgieva et al., 2006). CNP could be considered a potential biomarker for SCZ, since mRNA and protein alteration have been described in different brain regions (Table 2). Transferrin (TF) is highly expressed in oligodendrocytes and a number of transcriptome reports and proteome analyses have found it to be regulated (Table 2). TF, which main role is to transport iron ions, has a pivotal role for oligodendrocytes during myelination (Connor, 1994). Experiments conducted in young rats showed that TF concentrations increase when there is an iron deficiency (Erikson et al., 1997). These data, together with TPA findings regarding TF differential expression, have led to experiments in iron deficiency in SCZ. Recently, Insel et al. (2008) suggested that maternal iron deficiency may be a risk factor for SCZ in the offspring. This example shows how TPA findings can lead to other conclusive experiments. A number of transcriptome studies found oligodendrocyte-specific proteins, such as gelsolin (GSN), myelin and lymphocyte protein (MAL), claudin 11 (CLDN11), proteolipid protein (PLP) and quaking protein (QK1), to be regulated, suggesting an overall dysregulation of the oligodendrocyte metabolism and disturbed myelination (Table 2). Transcriptome analysis by Tkachev et al. (2003) found myelin basic protein (MBP) to be regulated in the prefrontal cortex (PFC) and our group found differential protein regulation of MBP in the DLPFC and anterior temporal lobe (ATL) (Martins-deSouza et al., 2009b,c). MBP is the major constituent of the myelin sheath of oligodendrocytes and Schwann cells in the nervous system. Even though Kuritzky et al. (1976), studying cellular-mediated immune response against MBP, already found a possible role for MBP in SCZ, the role of MBP in SCZ pathogenesis did not emerge until more than 20 years later, when it was confirmed by TPA.
Fig. 1. The protein network interaction of the differentially expressed oligodendrocyte-related genes and proteins in brain tissue in SCZ patients analyzed by the web-based software STRING (http://string.embl.de). 1A represents the direct interactions of the proteins listed in Table 2. 2A and C represents the direct interactions with other proteins, some of which are also revealed by TPA of brain tissue in SCZ patients, such as actin and the NOGO receptor (RTN4R).
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Fig. 1 (continued)
MOG is a membrane protein localized in the oligodendrocyte and myelin sheath surface; it has active roles in CNS development and synaptic transmission (Amiguet et al., 1992). As described above, MOG has a genetic association in the Chinese Han population (Liu et al., 2005), and the differential regulation of mRNA and protein in the Caucasian population leads us to assume the importance of MOG in SCZ pathogenesis. Moreover, MOG, as well as other genes and proteins described above such as MBP, are known markers for neurodegenerative diseases such as Multiple Sclerosis (MS).
6. Schizophrenia and neurodegeneration Most of researchers consider SCZ to be a neurodevelopmental disease, supporting the theory that the disruption of the normal neuronal development leads to neuronal malfunctioning. However, there are some researchers claiming that neurodegenerative events can occur in SCZ (Lieberman, 1999). Briefly, neurodegeneration is characterized by gliosis and neuron degeneration. In SCZ, glial proliferation has not been observed to the same extent that it has been in classical neurodegenerative disorders (Sawa and Kamiya, 2003), leading researchers to discard neurodegeneration as a feature of SCZ. However, there are some contrasting evidences. In his review, Lieberman (1999) have defended that clinical evidences regarding patient’s premorbid stage,
the illness course, symptoms and cognitive functions suggests neurodegenerative events in SCZ. Recently, in vivo neuroimaging studies have suggested that SCZ patients display progressive losses of gray matter in the frontal and temporal brain cortices, probably due to abnormal apoptotic events (Csernansky, 2007). Wojda et al. (2008) reviewed the main findings regarding calcium imbalance discussing how this can lead to degenerative processes as a result of dysfunctions in intracellular calcium buffering, storage and influx. Calcium imbalance has already been suggested in SCZ (Reynolds et al., 2004; Wojda et al., 2008). TPA of distinct brain tissues from SCZ patients has shown weak evidences regarding neurodegeneration process in SCZ. Evidences might be the differential expression in SCZ brain tissue of mRNA and proteins such as MBP, MOG, PLP and MAG (Table 2), which are classic markers of MS, one of the classical neurodegenerative disorders.
7. Protein association analysis Analyses of protein interaction were conducted on the proteins from Table 2 as shown in Fig. 1 in three levels, using the web-based software STRING (http://string.embl.de) (Jensen et al., 2009). It is possible to realize the intricate web of connections in which these differentially expressed genes and proteins participate, leading us
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Fig. 1 (continued)
to consider the complexity of the regulation of these proteins and which genes and proteins are the causes or consequences of the presented differential regulation. Further studies are needed in order to analyze the potential role of these genes and proteins in SCZ pathogenesis.
tially supported by previous clinical, imaging and molecular data from SCZ patients (Lieberman, 1999). The TPA data shown in Table 2 and Fig. 1 reinforce previous findings regarding oligodendrocyte dysfunction, allowing researchers to take a step forward in the comprehension of SCZ pathogenesis. Conflict of interest
8. Final remarks The author declares no conflicts of interest. It is important to remark that TPA experiments are more than just biomarker discovery tools not only for SCZ, but for all clinical studies. Identifying genes and proteins that are differentially expressed and validating those using alternative methods in a large number of samples can shed light on the diseases mechanisms. Systems biology analyses using the players revealed by TPA in a manner similar to that used for the differentially expressed genes and proteins in SCZ, presented in Table 2 (Fig. 1), might lead to a better understanding of the disease, indicating what will facilitate the diagnosis, treatment and in some cases, prevention. Here it has been shown the differential expression of genes and proteins related to oligodendrocyte metabolism in SCZ which have also been described in MS studies. This fact might lead to a primary understanding of SCZ as a neurodegenerative disease, an idea that is par-
Contributors DMS is the only contributor. Role of funding source This study was supported by MPG (Max Planck Gesellschaft). Acknowledgments I dedicate this article to the schizophrenia patients, tissue donors and their families. I would like to thank Prof. Dr. Chris W. Tur-
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Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires
Review
Proteome and transcriptome analysis suggests oligodendrocyte dysfunction in schizophrenia Daniel Martins-de-Souza * Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, D-80804 Munich, Germany
a r t i c l e
i n f o
Article history: Received 8 April 2009 Received in revised form 23 July 2009 Accepted 24 July 2009
Keywords: Schizophrenia Oligodendrocytes Myelin Proteome Proteomics Transcriptome Neurodegeneration
a b s t r a c t Despite all the efforts regarding the treatment of schizophrenia patients and the growing advances in molecular diagnosis studies, the biochemical basis of this debilitating psychotic mental disorder that affects approximately 1% of the world’s population is still not completely comprehended. Several recent clinical and molecular studies, using transcriptome and proteome analyses (TPA), for example, have described the oligodendrocyte dysfunction as a significant feature of the disease. TPA has been extensively used as a biomarker discovery tool, but a detailed and careful interpretation of the generated data can also provide a picture of the integrated biochemical systems that lead to the disease. This review presents the oligodendrocyte role players in schizophrenia pathogenesis as revealed by transcriptome and proteome studies. The presented data contribute to the composition of a scenario that may lead to a better understanding of schizophrenia pathogenesis. Ó 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8.
Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oligodendrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schizophrenia and oligodendrocytes: previous findings . . . . . . . . . Transcriptome and proteome analysis . . . . . . . . . . . . . . . . . . . . . . . Transcriptome and proteome analysis of brain tissue revealed the Schizophrenia and neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . Protein association analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Schizophrenia Schizophrenia (SCZ) is a debilitating, psychotic mental disorder that affects about 1% of the population worldwide (Freedman, 2003). It is a multifactorial disease, characterized by a series of negative and positive symptoms such as auditory and visual hallucinations, slow and disorganized thoughts, difficulty of understanding, memory deficit, difficulty of integrating feelings and * Tel.: +49 89 30622 630; fax: +49 89 30622 200. E-mail address: [email protected] 0022-3956/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2009.07.007
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behavior, paranoid delusions and significant social dysfunction that generally occur in young adulthood and, once present, usually persist for the patient’s lifetime (Sawa and Snyder, 2002). A diagnosis of SCZ is essentially made on the basis of clinical symptoms since it has an undefined molecular basis and there is a general lack of biochemical markers (Frances et al., 1991). SCZ is the result of multifactorial endogenous and exogenous interaction. The genetic components are probably the most important endogenous elements of this network, since DNA alterations, which have already been described in SCZ, may lead to differential gene and protein expression. As consequence, physiological
Shotgun 5 SCZ; 4 controls Martins-de-Souza et al. (2009c) – – Anterior temporal lobe (BA38)
–
1) Katsel et al. (2005) 2) McCullumsmith et al. (2007) Anterior Cingulate Cortex (BA24)
Abbreviations used: qPCR: real-time PCR; 2DE: two-dimensional gel electrophoresis; DIGE: differential in gel electrophoresis. a Katsel et al. (2005) studied regions: parietal (BA7), superior frontal gyrus (BA8), frontal cortex (BA10), occipital (BA17), inferior temporal gyrus (BA20), middle temporal gyrus (BA21), superior temporal gyrus (BA22), posterior cingulate (BA:23/31), anterior cingulate (BA32), parahippocampal gyrus (BA:36/28), insular cortex (BA44), hippocampus, caudate nucleus, caudate putamen.
–
2DE 10 SCZ; 10 controls
– –
Clark et al. (2006) 1) Microarray 2) In situ hybridization
qPCR Aberg et al. (2006a,b) Frontal Cortex (BA8)
1) 16 SCZ; 14 controls 2) 41 SCZ; 34 Controls
Dracheva et al. (2006) I – Cingulate Gyrus (Brodmann area 24/32) II – Hippocampus III – Caudate Nucleus IV – Caudate Putamen
55 SCZ; 55 CTRL
– – – qPCR
Katsel et al. (2005) Several regions a
I – 30 SCZ; 25 Controls II – 24 SCZ; 21 Controls III – 23 SCZ; 20 Controls IV – 24 SCZ; 19 Controls
–
– –
– –
– Microarray
Microarray Aston et al. (2004) Temporal cortex (middle temporal gyrus – BA21)
16 SCZ; 14 controls
Tkachev et al. (2003)
12 SCZ; 14 controls
1) 2DE-DIGE 2) 2DE 1) 54 SCZ; 50 controls 2) 35 SCZ; 35 controls 1) Prabakaran et al. (2004) 2) Pennington et al. (2008) Microarray
Methodology
Prefrontal cortex (BA9)
15 SCZ; 15 controls
1) 9 SCZ; 7 controls 2) 9 SCZ; 7 controls
Subjects Proteome Reference Methodology Subjects
1) Hakak et al. (2001) 2) Katsel et al. (2005) 3) Arion et al. (2007)
Transcriptomics and proteomics are ‘‘young sciences” whose names arose from the terms ‘‘transcriptome” and ‘‘proteome” (Velculescu et al., 1997; Wilkins et al., 1996a,b). These sciences can be defined as ‘‘the study of the total set of expressed transcripts and proteins by a genome, cell, tissue or organism at a given time under a determined condition”. Since nowadays these sciences are more complex and complete and so do more than just
Transcriptome reference
4. Transcriptome and proteome analysis
Dorso-lateral prefrontal cortex (BA46)
Brain imaging studies have demonstrated the dysfunction of oligodendrocytes in SCZ. Using magnetic transfer imaging, Foong et al. (2000), studying the temporal lobe, and Kubicki et al. (2005), studying the frontal lobe, have analyzed white matter integrity and found decreased myelin integrity, as well as decreased axonal membranes. In addition, abnormal distribution and decreased density of oligodendrocytes, apoptotic oligodendrocytes, damaged myelin sheaths and a decreased volume density of mitochondria were observed by electron microscopy studies in frontal regions of SCZ brains (Uranova et al., 2001). Decreased levels of phosphatidylcholine, sphingomyelin and galactocerebroside, which play indispensable roles in oligodendrocyte metabolism, were found in the post-mortem thalamus of patients with SCZ (Schmitt et al., 2004). Epigenetic evidence has also shown the potential role of oligodendrocytes in SCZ. Iwamoto et al. (2005) found hypermethylation of gene SOX10, which can lead to an overexpression of structural myelin proteins (Chan et al., 2003) in SCZ patients. Moreover, Liu et al. (2005) described the positive association of the myelin oligodendrocyte glycoprotein (MOG) gene with SCZ in the Chinese Han population, although Zai et al. (2005) did not find the same association in a group of SCZ patients composed by 95% Caucasian subjects. MOG had been previously associated with white matter abnormalities in SCZ, and has a role in the complement cascade (Davis et al., 2003 for review; Hof et al., 2003). Karoutzou et al. (2008) has presented a detailed review of linkage studies and susceptible genes oligodendrocyte-related in SCZ as well as oligodendrocyte-related genes that have already been associated with SCZ.
Table 1 Analysis of gene and proteome expression of post-mortem SCZ brain tissue which have suggested oligodendrocytes dysfunctions.
3. Schizophrenia and oligodendrocytes: previous findings
1) Martins-de-Souza et al. (2009b) 2) Martins-de-Souza et al. (2009a)
Oligodendrocytes are a type of neuroglia constituting approximately 51% of the cells around the soma of large neurons in the human cortex (Polak et al., 1982); their main function is to insulate the axons in the central nervous system (CNS), wrapping it with myelin, providing an electrically-insulating phospholipid layer that facilitate axonal signal by increasing the speed at which the electrical impulses are propagated and by preventing the electrical current from leaving the axon. Trophic signaling among neurons, growth factor synthesis, neuronal survival and development and neurotransmission are other oligodendrocyte functions (Du and Dreyfus, 2002; Deng and Poretz, 2003). A disturbance in the myelin sheath could lead to ion leakage with reduced nerve impulse propagation, consequently compromising neuronal and glial functions. Convergent data from different research fields have described the dysfunction of oligodendrocytes as an important feature in SCZ pathogenesis because of their implication in brain connectivity. Recently, dysfunctions of oligodendrocyte metabolism have been often observed and suggested in SCZ studies of brain tissue (Segal et al., 2007 for review).
1) Microarray 2) Microarray 3) Microarray
2. Oligodendrocytes
1) 12 SCZ; 12 controls 2) 16 SCZ; 14 controls 3) 12 SCZ; 12 controls
imbalances are driven that, combined with environmental factors, trigger the disease. Despite all the clinical and molecular efforts to understand SCZ, some features remain undiscovered.
1) 2DE 2) Shotgun
D. Martins-de-Souza / Journal of Psychiatric Research 44 (2010) 149–156
Brain region
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identify a complete set of differentially expressed proteins and genes, from now on in this article, transcriptome and proteome analyses (TPA) will be defined as a tool for identifying differentially expressed genes and proteins in pathological states. Most of the transcriptome analyses performed on the brain tissue of SCZ patients have been conducted using cDNA microarray analysis, one of the most powerful tools for large-scale gene expression investigation in human diseases. Some advantages of microarray analysis are that it allows large-scale automated evaluation of thousands of transcripts, requires relatively small amounts of RNA and has low bioinformatics requirements. However, some drawbacks are observed such as only the transcripts present in the array are evaluated (which means unknown genes are not analyzed), complex statistical analysis, high false positive rate and difficulty to perform multiple comparisons. In SCZ transcriptome analysis, real-time PCR (qPCR), Northern blots and in situ hybridization have been used as validation methods.
Most of the proteome analyses of brain tissue of SCZ patients were performed using a combination of two-dimensional gel electrophoresis (2DE) to separate the proteins and mass spectrometry to identify the differentially expressed proteins. The combination of 2DE and mass spectrometry allows the separation of thousands of proteins in a single experiment, a direct software-based comparison of 2DE gels from different samples (i.e. controls versus disease samples) and the unambiguous identification of the proteins. However, it is known that there is a bias towards the highly expressed proteins in 2DE profiles. In addiction, it is difficulty to detect in 2DE profiles extremely acid and extremely basic proteins as well as proteins with very high and very low molecular weights. Shotgun proteomics, which enriches the low-expressed proteins in a high throughput way, has also been used to study brain tissue in SCZ. Western blot, ELISA and antibody arrays have been performed to validate the proteomics findings.
Table 2 Oligodendrocyte-related genes and proteins with altered expression in SCZ brain tissues. Protein name
Gene
Transcriptome alteration
Proteome alteration
Transferrin
TF
Hakak et al. (2001) Tkachev et al. (2003) Katsel et al. (2005) Aberg et al. (2006b) McCullumsmith et al. (2007) Arion et al. (2007)
Prabakaran et al. (2004) Clark et al. (2006) Pennington et al. (2008) Martins-de-Souza et al. (2009b)
20 ,30 -Cyclic nucleotide 30 -phosphodiesterase
CNP
Hakak et al. (2001) Tkachev et al. (2003) Aston et al. (2004) Katsel et al. (2005) Dracheva et al. (2006) McCullumsmith et al. (2007)
Flynn et al. (2003) Prabakaran et al. (2004) Martins-de-Souza et al. (2009a) Martins-de-Souza et al. (2009c)
Myelin basic protein
MBP
Tkachev et al. (2003) Sugai et al. (2004)
Chambers and Perrone-Bizzozero (2004) Martins-de-Souza et al. (2009b) Martins-de-Souza et al. (2009c)
Myelin oligodendrocyte glycoprotein
MOG
Tkachev et al. (2003) Katsel et al. (2005) Arion et al. (2007)
Martins-de-Souza et al. (2009a) Martins-de-Souza et al. (2009c)
Gelsolin
GSN
Hakak et al. (2001) Katsel et al. (2005)
Prabakaran et al. (2004)
Myelin-associated glycoprotein
MAG
Hakak et al. (2001) Tkachev et al. (2003) Aston et al. (2004) Katsel et al. (2005) Aberg et al. (2006b) Dracheva et al. (2006)
–
V-erb-b2 erythroblastic leukemia viral oncogene
ERBB3
McCullumsmith et al. (2007) Hakak et al. (2001) Tkachev et al. (2003) Aston et al. (2004) Katsel et al. (2005)
–
T-Lymphocyte maturation-associated protein
MAL
Hakak et al. (2001) Aston et al. (2004) Sugai et al. (2004) Katsel et al. (2005)
–
Claudin 11; Oligodendrocyte specific protein
CLDN11
Tkachev et al. (2003) Katsel et al. (2005) Dracheva et al. (2006) Weidenhofer et al. (2006)
–
Proteolipid protein
PLP
Tkachev et al. (2003) Aston et al. (2004) Aberg et al. (2006b)
–
Plasmolipin or transmembrane 4 superfamily 11
PLLP/TM4SF11
Aston et al. (2004) Katsel et al. (2005)
–
Quaking homolog
QKI
Aberg et al. (2006a) McCullumsmith et al. (2007) Haroutunian et al. (2006)
–
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TPA of brain tissue in SCZ patients has consistently revealed the differential expression of different classes of genes and proteins, such as those related to oligodendrocytes.
5. Transcriptome and proteome analysis of brain tissue revealed the oligodendrocyte players in schizophrenia TPA has been extensively used to reveal potential SCZ biomarkers in human samples. However, TPA findings can be used not only to reveal biomarkers, but also to identify the players in SCZ pathogenesis, which could lead to better comprehension and elucidation of the disease mechanisms. Consequently, new doors to new research directions will be opening, leading to more specific goals. TPA of brain tissue has revealed potential oligodendrocyte dysfunction in SCZ as well as in other psychiatric disorders, such as major depression (Aston et al., 2005). Studies of neurodevelopment and synaptic circuits in several brain regions from SCZ patients have also found the dysfunction of oligodendrocytes in SCZ (Honer et al., 1999; Flynn et al., 2003; Beasley et al., 2009). Oligodendrocyte dysfunction in SCZ discovered by transcriptome studies in post-mortem tissue was first presented by Hakak et al. (2001) studying the gray matter of the dorsolateral prefrontal cortex (DLPFC), Brodmann’s Area (BA) 46 from 12 SCZ patients and 12 controls (CTRL) as shown in Table 2. Afterwards, subsequent transcriptome analyses corroborated with these findings in the gray and white matter of the prefrontal cortex (BA9) from 15 SCZ patients and 15 CTRL subjects (Tkachev et al., 2003), in the gray and white matter of the middle temporal gyrus (BA21) from 12 SCZ subjects and 14 matched CTRL (Aston et al., 2004) and in the gray and white matter of the DLPFC (BA46) from 12 SCZ subjects and 12 CTRL subjects (Arion et al., 2007). Microarray experiments in multiple cortical and non-cortical regions (Katsel et al., 2005) and validation experiments using real-time PCR and in situ hybridization have been performed in the gray and white matter of multiple samples from the brain regions described in Table 1 (Aberg et al., 2006a,b; Dracheva et al., 2006; McCullumsmith et al., 2007) and the dysfunction in oligodendrocytes metabolism have also been found. The first proteome report concerning oligodendrocyte dysfunction in SCZ was published by Prabakaran et al. (2004) studying gray and white matter of the DLPFC (BA9) from 54 SCZ and 50 CTRL. Subsequent proteome experiments (Table 1) were able to corroborate previous data and even present new oligodendrocyte candidates (Table 2). All the reports described above did not differentiated oligodendrocytes from gray and white matter. All the transcriptome reports shown here (Table 1) have found differential regulation of the myelin-associated glycoprotein (MAG), an indispensable membrane protein in the myelination process and post-natal neural development. However, no proteome reports found differential expression of MAG, which has an isoelectric point (pI) of 4.97 and a molecular weight (MW) of 69,068.52 (theoretical data), so that it should be easily identifiable using available proteomics methods. This suggests that a transcriptional regulation event could change the mRNA concentration of this gene that could be a potential mRNA biomarker. 20 ,30 -cyclic nucleotide 30 -phosphodiesterase (CNP) was found differentially expressed in six transcriptome analyses and three proteome analyses of SCZ brain tissue. CNP is a membrane-bound microtubule-associated protein which links tubulin to cellular membranes regulating the microtubule distribution in the cytoplasm (Bifulco et al., 2002). CNP is a well-characterized marker of myelin-forming cells and in oligodendrocytes interacts with tubulin promoting microtubule assembly for process outgrowth (Lee et al., 2005). Moreover, CNP plays an indispensable role not only in oligodendrocytes but also in axonogenesis (Higuchi et al.,
2005; Kursula, 2008), in cyclic nucleotide catabolic process (Drummond et al., 1962), RNA metabolic process (Boccaccio and Colman, 1995), microtubule cytoskeleton organization and synaptic transmission (Sprinkle et al., 1992; Monoh et al., 1993). Genetic association studies have confirmed the potential CNP role in SCZ pathogenesis (Peirce et al., 2006; Georgieva et al., 2006). CNP could be considered a potential biomarker for SCZ, since mRNA and protein alteration have been described in different brain regions (Table 2). Transferrin (TF) is highly expressed in oligodendrocytes and a number of transcriptome reports and proteome analyses have found it to be regulated (Table 2). TF, which main role is to transport iron ions, has a pivotal role for oligodendrocytes during myelination (Connor, 1994). Experiments conducted in young rats showed that TF concentrations increase when there is an iron deficiency (Erikson et al., 1997). These data, together with TPA findings regarding TF differential expression, have led to experiments in iron deficiency in SCZ. Recently, Insel et al. (2008) suggested that maternal iron deficiency may be a risk factor for SCZ in the offspring. This example shows how TPA findings can lead to other conclusive experiments. A number of transcriptome studies found oligodendrocyte-specific proteins, such as gelsolin (GSN), myelin and lymphocyte protein (MAL), claudin 11 (CLDN11), proteolipid protein (PLP) and quaking protein (QK1), to be regulated, suggesting an overall dysregulation of the oligodendrocyte metabolism and disturbed myelination (Table 2). Transcriptome analysis by Tkachev et al. (2003) found myelin basic protein (MBP) to be regulated in the prefrontal cortex (PFC) and our group found differential protein regulation of MBP in the DLPFC and anterior temporal lobe (ATL) (Martins-deSouza et al., 2009b,c). MBP is the major constituent of the myelin sheath of oligodendrocytes and Schwann cells in the nervous system. Even though Kuritzky et al. (1976), studying cellular-mediated immune response against MBP, already found a possible role for MBP in SCZ, the role of MBP in SCZ pathogenesis did not emerge until more than 20 years later, when it was confirmed by TPA.
Fig. 1. The protein network interaction of the differentially expressed oligodendrocyte-related genes and proteins in brain tissue in SCZ patients analyzed by the web-based software STRING (http://string.embl.de). 1A represents the direct interactions of the proteins listed in Table 2. 2A and C represents the direct interactions with other proteins, some of which are also revealed by TPA of brain tissue in SCZ patients, such as actin and the NOGO receptor (RTN4R).
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Fig. 1 (continued)
MOG is a membrane protein localized in the oligodendrocyte and myelin sheath surface; it has active roles in CNS development and synaptic transmission (Amiguet et al., 1992). As described above, MOG has a genetic association in the Chinese Han population (Liu et al., 2005), and the differential regulation of mRNA and protein in the Caucasian population leads us to assume the importance of MOG in SCZ pathogenesis. Moreover, MOG, as well as other genes and proteins described above such as MBP, are known markers for neurodegenerative diseases such as Multiple Sclerosis (MS).
6. Schizophrenia and neurodegeneration Most of researchers consider SCZ to be a neurodevelopmental disease, supporting the theory that the disruption of the normal neuronal development leads to neuronal malfunctioning. However, there are some researchers claiming that neurodegenerative events can occur in SCZ (Lieberman, 1999). Briefly, neurodegeneration is characterized by gliosis and neuron degeneration. In SCZ, glial proliferation has not been observed to the same extent that it has been in classical neurodegenerative disorders (Sawa and Kamiya, 2003), leading researchers to discard neurodegeneration as a feature of SCZ. However, there are some contrasting evidences. In his review, Lieberman (1999) have defended that clinical evidences regarding patient’s premorbid stage,
the illness course, symptoms and cognitive functions suggests neurodegenerative events in SCZ. Recently, in vivo neuroimaging studies have suggested that SCZ patients display progressive losses of gray matter in the frontal and temporal brain cortices, probably due to abnormal apoptotic events (Csernansky, 2007). Wojda et al. (2008) reviewed the main findings regarding calcium imbalance discussing how this can lead to degenerative processes as a result of dysfunctions in intracellular calcium buffering, storage and influx. Calcium imbalance has already been suggested in SCZ (Reynolds et al., 2004; Wojda et al., 2008). TPA of distinct brain tissues from SCZ patients has shown weak evidences regarding neurodegeneration process in SCZ. Evidences might be the differential expression in SCZ brain tissue of mRNA and proteins such as MBP, MOG, PLP and MAG (Table 2), which are classic markers of MS, one of the classical neurodegenerative disorders.
7. Protein association analysis Analyses of protein interaction were conducted on the proteins from Table 2 as shown in Fig. 1 in three levels, using the web-based software STRING (http://string.embl.de) (Jensen et al., 2009). It is possible to realize the intricate web of connections in which these differentially expressed genes and proteins participate, leading us
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Fig. 1 (continued)
to consider the complexity of the regulation of these proteins and which genes and proteins are the causes or consequences of the presented differential regulation. Further studies are needed in order to analyze the potential role of these genes and proteins in SCZ pathogenesis.
tially supported by previous clinical, imaging and molecular data from SCZ patients (Lieberman, 1999). The TPA data shown in Table 2 and Fig. 1 reinforce previous findings regarding oligodendrocyte dysfunction, allowing researchers to take a step forward in the comprehension of SCZ pathogenesis. Conflict of interest
8. Final remarks The author declares no conflicts of interest. It is important to remark that TPA experiments are more than just biomarker discovery tools not only for SCZ, but for all clinical studies. Identifying genes and proteins that are differentially expressed and validating those using alternative methods in a large number of samples can shed light on the diseases mechanisms. Systems biology analyses using the players revealed by TPA in a manner similar to that used for the differentially expressed genes and proteins in SCZ, presented in Table 2 (Fig. 1), might lead to a better understanding of the disease, indicating what will facilitate the diagnosis, treatment and in some cases, prevention. Here it has been shown the differential expression of genes and proteins related to oligodendrocyte metabolism in SCZ which have also been described in MS studies. This fact might lead to a primary understanding of SCZ as a neurodegenerative disease, an idea that is par-
Contributors DMS is the only contributor. Role of funding source This study was supported by MPG (Max Planck Gesellschaft). Acknowledgments I dedicate this article to the schizophrenia patients, tissue donors and their families. I would like to thank Prof. Dr. Chris W. Tur-
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