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Oxidative stress and dysregulated Nrf2 activation in the pathogenesis of schizophrenia
Bioscience Hypotheses (2009) 2, 16e18 available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
Oxidative stress and dysregulated Nrf2 activation in the pathogenesis of schizophrenia Kursad Genc a,*, Sermin Genc a,b a b
Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Inciralti, 35340 Izmir, Turkey Research Laboratory, School of Medicine, Dokuz Eylul University, Inciralti, 35340 Izmir, Turkey
Received 14 October 2008; received in revised form 20 October 2008; accepted 23 October 2008
KEYWORDS Schizophrenia; Oxidative stress; Neuroinflammation; Nrf2; Brain-derived neurotrophic factor; DISC1; ATF4; Glycogen synthase kinase-3
Abstract Several processes including oxidative stress and neuroinflammation are implicated in the pathogenesis of schizophrenia. The dysregulated activation of a transcription factor, nuclear factor-E2-related factor-2 (Nrf2) which regulates the expression and coordinated induction of a battery of cytoprotective, antioxidant, and anti-inflammatory genes in response to oxidative stress and inflammation, might play a critical role in the pathogenesis of schizophrenia. ª 2008 Elsevier Ltd. All rights reserved.
Neuroinflammation, disturbed neurogenesis, glutamergic, dopaminergic, and GABAergic dysregulation, and brainderived neurotrophic factor (BDNF) production defects have all been implicated in the pathogenesis of schizophrenia [7]. Herein, we propose that the dysregulated activation of a transcription factor, nuclear factor-E2related factor-2 (Nrf2), is related to most of these factors and plays a critical role in the pathogenesis of schizophrenia. Nrf2 activation protects neural, glial and endothelial cells against oxidative stress and inflammation [1,15].
* Corresponding author. Tel.: þ90 232 412 2604; fax: þ90 232 277 6584. E-mail address: [email protected] (K. Genc).
According to the neurogliovascular-inflammatory theory, a variety of environmental insults, such as infection may follow a common final pathway to psychopathology by stimulating inflammatory processes that damage the neurogliovascular unit [5]. Inflammation-related genes upregulate in schizophrenia brains [12]. The protective effect of Nrf2 activation has also been demonstrated in neural stem cells in vitro [9]. Thus, impaired neurogenesis may be related to Nrf2 dysregulation in schizophrenia. Dysregulated Nrf2 activation has been reported in neurodegenerative disorders, in which oxidative stress is a common pathogenic mechanism [11]. Glutathione, a redox regulator, is decreased in the cerebrospinal fluid and prefrontal cortex of schizophrenic patients [3,4]. The gene of the key glutathione-synthesizing enzyme, glutamate cysteine ligase modifier subunit, is a target gene of
1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.10.005
Oxidative stress and dysregulated Nrf2 activation
17
Figure 1 Simplified representation of the possible relationships between the Nrf2 pathway and schizophrenia-associated genes. Nrf2 is sequestered in the cytoplasm by Keap1, and is transcriptionally inactive until Keap1 is dissociated by reactive oxygen species (ROS). Then, Nrf2 translocates from the cytoplasm into the nucleus and forms transcriptionally active complexes with other proteins, such as small Maf proteins. Nrf2 regulates the expression and coordinated induction of a battery of cytoprotective, antioxidant, and anti-inflammatory genes in response to oxidative stress. Target genes of Nrf2 contain the antioxidant response element (ARE) in their promoter regions. Regulation of Nrf2 activation includes several steps such as diminished rate of proteolysis or enhanced nuclear accumulation. Nrf2 can also be activated by phosphorylation by kinases such as mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), or phosphatidylinositol 3-kinase (PI3K).
Nrf2 and strongly associated with schizophrenia [14]. Nevertheless, association with Nrf2 gene expression has not been found in schizophrenia [14]. But, this finding does not exclude a dysregulated Nrf2 activation state in the schizophrenic brain. One of the key features of schizophrenia is striatal hyperdopaminergia [7]. Dopamine at high (toxic) doses results in Nrf2 activation in vitro as a neuroprotective compensatory mechanism [13]. Schizophrenia is also characterised by astrocytic malfunction, and myelin and oligodendrocyte cell loss [2,7]. The main source of antioxidant enzymes in the brain is the astrocyte [1]. Astroglial involvement in schizophrenia may result in impaired Nrf2 activation. Nrf2 may also play a possible physiologic role in myelination [6]. Neuron-specific Nrf2 down-stream genes (other than the classic antioxidant genes) including BDNF, GABA receptors, and synaptic proteins, may substantially contribute to protection against schizophrenia (Fig. 1) [1]. Another molecule implicated in schizophrenia, glycogen synthase kinase-3 (GSK-3) beta, inhibits the antioxidant cell response by direct phosphorylation and nuclear exclusion of Nrf2 [8,10]. Thus, GSK-3 dysregulation in schizophrenia may result in functional alteration of the Nrf2 pathway. Certain high-interest genes in schizophrenia may be interconnected with the antioxidant defense system [2]. One product of them, DISC1, binds to the
activation transcription factor 4 (ATF4). ATF4 regulates the transcription of glutathione-related genes, controls the ability of cells to resist oxidative stress and binds to Nrf2 [2]. However, the impact of these interactions is not clear (Fig. 1). Further postmortem studies, and in vitro and in vivo experimental studies should be conducted to test the hypothesis proposed here.
References [1] Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, et al. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 2008 Aug 21 [Epub ahead of print]. [2] Carter CJ. Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr Res 2006;86:1e14. [3] Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000;12:3721e8. [4] Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A 2007;104:16621e6. [5] Hanson DR, Gottesman II. Theories of schizophrenia: a geneticinflammatory-vascular synthesis. BMC Med Genet 2005;6:7.
18 [6] Hubbs AF, Benkovic SA, Miller DB, O‘Callaghan JP, Battelli L, Schwegler-Berry D, et al. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am J Pathol 2007;170:2068e76. [7] Jarskog LF, Miyamoto S, Lieberman JA. Schizophrenia: new pathological insights and therapies. Annu Rev Med 2007;58: 49e61. [8] Jain AK, Jaiswal AK. GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem 2007;282:16502e10. [9] Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 2005;83:313e28. [10] Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 2007;30:142e9.
K. Genc, S. Genc [11] Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, et al. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 2007;66:75e85. [12] Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E. Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry 2007;7:46. [13] Shih AY, Erb H, Murphy TH. Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cells. J Neurochem 2007;101:109e19. [14] Tosic M, Ott J, Barral S, Bovet P, Deppen P, Gheorghita F, et al. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet 2006;79: 586e92. [15] Zhao J, Moore AN, Redell JB, Dash PK. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 2007;27:10240e8.
journal homepage: www.elsevier.com/locate/bihy
Oxidative stress and dysregulated Nrf2 activation in the pathogenesis of schizophrenia Kursad Genc a,*, Sermin Genc a,b a b
Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Inciralti, 35340 Izmir, Turkey Research Laboratory, School of Medicine, Dokuz Eylul University, Inciralti, 35340 Izmir, Turkey
Received 14 October 2008; received in revised form 20 October 2008; accepted 23 October 2008
KEYWORDS Schizophrenia; Oxidative stress; Neuroinflammation; Nrf2; Brain-derived neurotrophic factor; DISC1; ATF4; Glycogen synthase kinase-3
Abstract Several processes including oxidative stress and neuroinflammation are implicated in the pathogenesis of schizophrenia. The dysregulated activation of a transcription factor, nuclear factor-E2-related factor-2 (Nrf2) which regulates the expression and coordinated induction of a battery of cytoprotective, antioxidant, and anti-inflammatory genes in response to oxidative stress and inflammation, might play a critical role in the pathogenesis of schizophrenia. ª 2008 Elsevier Ltd. All rights reserved.
Neuroinflammation, disturbed neurogenesis, glutamergic, dopaminergic, and GABAergic dysregulation, and brainderived neurotrophic factor (BDNF) production defects have all been implicated in the pathogenesis of schizophrenia [7]. Herein, we propose that the dysregulated activation of a transcription factor, nuclear factor-E2related factor-2 (Nrf2), is related to most of these factors and plays a critical role in the pathogenesis of schizophrenia. Nrf2 activation protects neural, glial and endothelial cells against oxidative stress and inflammation [1,15].
* Corresponding author. Tel.: þ90 232 412 2604; fax: þ90 232 277 6584. E-mail address: [email protected] (K. Genc).
According to the neurogliovascular-inflammatory theory, a variety of environmental insults, such as infection may follow a common final pathway to psychopathology by stimulating inflammatory processes that damage the neurogliovascular unit [5]. Inflammation-related genes upregulate in schizophrenia brains [12]. The protective effect of Nrf2 activation has also been demonstrated in neural stem cells in vitro [9]. Thus, impaired neurogenesis may be related to Nrf2 dysregulation in schizophrenia. Dysregulated Nrf2 activation has been reported in neurodegenerative disorders, in which oxidative stress is a common pathogenic mechanism [11]. Glutathione, a redox regulator, is decreased in the cerebrospinal fluid and prefrontal cortex of schizophrenic patients [3,4]. The gene of the key glutathione-synthesizing enzyme, glutamate cysteine ligase modifier subunit, is a target gene of
1756-2392/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.10.005
Oxidative stress and dysregulated Nrf2 activation
17
Figure 1 Simplified representation of the possible relationships between the Nrf2 pathway and schizophrenia-associated genes. Nrf2 is sequestered in the cytoplasm by Keap1, and is transcriptionally inactive until Keap1 is dissociated by reactive oxygen species (ROS). Then, Nrf2 translocates from the cytoplasm into the nucleus and forms transcriptionally active complexes with other proteins, such as small Maf proteins. Nrf2 regulates the expression and coordinated induction of a battery of cytoprotective, antioxidant, and anti-inflammatory genes in response to oxidative stress. Target genes of Nrf2 contain the antioxidant response element (ARE) in their promoter regions. Regulation of Nrf2 activation includes several steps such as diminished rate of proteolysis or enhanced nuclear accumulation. Nrf2 can also be activated by phosphorylation by kinases such as mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), or phosphatidylinositol 3-kinase (PI3K).
Nrf2 and strongly associated with schizophrenia [14]. Nevertheless, association with Nrf2 gene expression has not been found in schizophrenia [14]. But, this finding does not exclude a dysregulated Nrf2 activation state in the schizophrenic brain. One of the key features of schizophrenia is striatal hyperdopaminergia [7]. Dopamine at high (toxic) doses results in Nrf2 activation in vitro as a neuroprotective compensatory mechanism [13]. Schizophrenia is also characterised by astrocytic malfunction, and myelin and oligodendrocyte cell loss [2,7]. The main source of antioxidant enzymes in the brain is the astrocyte [1]. Astroglial involvement in schizophrenia may result in impaired Nrf2 activation. Nrf2 may also play a possible physiologic role in myelination [6]. Neuron-specific Nrf2 down-stream genes (other than the classic antioxidant genes) including BDNF, GABA receptors, and synaptic proteins, may substantially contribute to protection against schizophrenia (Fig. 1) [1]. Another molecule implicated in schizophrenia, glycogen synthase kinase-3 (GSK-3) beta, inhibits the antioxidant cell response by direct phosphorylation and nuclear exclusion of Nrf2 [8,10]. Thus, GSK-3 dysregulation in schizophrenia may result in functional alteration of the Nrf2 pathway. Certain high-interest genes in schizophrenia may be interconnected with the antioxidant defense system [2]. One product of them, DISC1, binds to the
activation transcription factor 4 (ATF4). ATF4 regulates the transcription of glutathione-related genes, controls the ability of cells to resist oxidative stress and binds to Nrf2 [2]. However, the impact of these interactions is not clear (Fig. 1). Further postmortem studies, and in vitro and in vivo experimental studies should be conducted to test the hypothesis proposed here.
References [1] Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, et al. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 2008 Aug 21 [Epub ahead of print]. [2] Carter CJ. Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr Res 2006;86:1e14. [3] Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000;12:3721e8. [4] Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A 2007;104:16621e6. [5] Hanson DR, Gottesman II. Theories of schizophrenia: a geneticinflammatory-vascular synthesis. BMC Med Genet 2005;6:7.
18 [6] Hubbs AF, Benkovic SA, Miller DB, O‘Callaghan JP, Battelli L, Schwegler-Berry D, et al. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am J Pathol 2007;170:2068e76. [7] Jarskog LF, Miyamoto S, Lieberman JA. Schizophrenia: new pathological insights and therapies. Annu Rev Med 2007;58: 49e61. [8] Jain AK, Jaiswal AK. GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem 2007;282:16502e10. [9] Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 2005;83:313e28. [10] Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 2007;30:142e9.
K. Genc, S. Genc [11] Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, et al. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 2007;66:75e85. [12] Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E. Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry 2007;7:46. [13] Shih AY, Erb H, Murphy TH. Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cells. J Neurochem 2007;101:109e19. [14] Tosic M, Ott J, Barral S, Bovet P, Deppen P, Gheorghita F, et al. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet 2006;79: 586e92. [15] Zhao J, Moore AN, Redell JB, Dash PK. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 2007;27:10240e8.