Abstract
The novel transcriptional repressor protein, R1 (JPO2/CDCA7L/RAM2), inhibits monoamine oxidase A (MAO A) gene expression and influences cell proliferation and survival. MAO A is implicated in several neuropsychiatric illnesses and highly elevated in major depressive disorder (MDD); however, whether R1 is involved in these disorders is unknown. This study evaluates the role of R1 in depressed subjects either untreated or treated with antidepressant drugs. R1 protein levels were determined in the postmortem prefrontal cortex of 18 untreated MDD subjects and 12 medicated MDD subjects compared with 18 matched psychiatrically normal control subjects. Western blot analysis showed that R1 was significantly decreased by 37.5% (p<0.005) in untreated MDD subjects. The R1 level in medicated MDD subjects was also significantly lower (by 30%; p<0.05) compared with control subjects, but was not significantly different compared with untreated MDD subjects. Interestingly, the reduction in R1 was significantly correlated with an increase (approximately 40%; p<0.05) in MAO A protein levels within the MDD groups compared with controls. Consistent with the change in MAO A protein expression, the MAO A catalytic activity was significantly greater in both MDD groups compared with controls. These results suggest that reduced R1 may lead to elevated MAO A levels in untreated and treated MDD subjects; moreover, the reduction of R1 has been implicated in apoptotic cell death and apoptosis has also been observed in the brains of MDD subjects. Therefore, modulation of R1 levels may provide a new therapeutic target in the development of more effective strategies to treat MDD.
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References
Andreazza AC, Shao L, Wang JF, Young LT (2010). Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder. Arch Gen Psychiatry 67: 360–368.
Bartholomeeusen K, De Rijck J, Busschots K, Desender L, Gijsbers R, Emiliani S et al (2007). Differential interaction of HIV-1 integrase and JPO2 with the C terminus of LEDGF/p75. J Mol Biol 372: 407–421.
Beck GJ, Doyle CA, Schachter EN (1981). Smoking and lung function. Am Rev Respir Dis 123: 149–155.
Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S et al (1995). Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science (New York, NY) 268: 1763–1766.
Chen K, Ou XM, Chen G, Choi SH, Shih JC (2005). R1, a novel repressor of the human monoamine oxidase A. J Biol Chem 280: 11552–11559.
Chen K, Ou XM, Wu JB, Shih JC (2011). Transcription factor E2F-associated phosphoprotein (EAPP), RAM2/CDCA7L/JPO2 (R1), and simian virus 40 promoter factor 1 (Sp1) cooperatively regulate glucocorticoid activation of monoamine oxidase B. Mol Pharmacol 79: 308–317.
Chouinard G, Young SN, Annable L (1985). A controlled clinical trial of L-tryptophan in acute mania. Biol Psychiatry 20: 546–557.
De Zutter GS, Davis RJ (2001). Pro-apoptotic gene expression mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Proc Natl Acad Sci USA 98: 6168–6173.
Deep-Soboslay A, Akil M, Martin CE, Bigelow LB, Herman MM, Hyde TM et al (2005). Reliability of psychiatric diagnosis in postmortem research. Biol Psychiatry 57: 96–101.
Dejong TM, Overholser JC (2009). Assessment of depression and suicidal actions: agreement between suicide attempters and informant reports. Suicide Life Threat Behav 39: 38–46.
Du L, Bakish D, Ravindran A, Hrdina PD (2004). MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males. Neuroreport 15: 2097–2101.
Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD (2002). High activity-related allele of MAO-A gene associated with depressed suicide in males. Neuroreport 13: 1195–1198.
Duman RS, Monteggia LM (2006). A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59: 1116–1127.
Dwivedi Y, Mondal AC, Rizavi HS, Faludi G, Palkovits M, Sarosi A et al (2006). Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Arch Gen Psychiatry 63: 639–648.
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN (2003). Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 60: 804–815.
Dwivedi Y, Rizavi HS, Zhang H, Mondal AC, Roberts RC, Conley RR et al (2009). Neurotrophin receptor activation and expression in human postmortem brain: effect of suicide. Biol Psychiatry 65: 319–328.
Egede LE (2004). Diabetes, major depression, and functional disability among U.S. adults. Diabetes Care 27: 421–428.
Fan M, Liu B, Jiang T, Jiang X, Zhao H, Zhang J (2010). Meta-analysis of the association between the monoamine oxidase-A gene and mood disorders. Psychiatr Genet 20: 1–7.
First MBSR, Gibbon M, Williams JBW (1996). Structured Clinical Interview for DSM-IV Axis I Disorders—Patient Edition, Version 2.0 ed. Biometrics Research Department, New York State Psychiatric Institute: New York.
Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, Shea C et al (1996). Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci USA 93: 14065–14069.
Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2010). Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14: 1–8.
Goridis C, Neff NH (1971). Monoamine oxidase in sympathetic nerves: a transmitter specific enzyme type. Br J Pharmacol 43: 814–818.
Greer S, Honeywell R, Geletu M, Arulanandam R, Raptis L (2010). Housekeeping genes; expression levels may change with density of cultured cells. J Immunol Meth 355: 76–79.
Huang A, Ho CS, Ponzielli R, Barsyte-Lovejoy D, Bouffet E, Picard D et al (2005). Identification of a novel c-Myc protein interactor, JPO2, with transforming activity in medulloblastoma cells. Cancer Res 65: 5607–5619.
Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA et al (2007). Gene expression profiling in postmortem prefrontal cortex of major depressive disorder. J Neurosci 27: 13329–13340.
Keller MB, Boland RJ (1998). Implications of failing to achieve successful long-term maintenance treatment of recurrent unipolar major depression. Biol Psychiatry 44: 348–360.
Kelly TM, Mann JJ (1996). Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatrica Scandinavica 94: 337–343.
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289: 3095–3105.
Klimek V, Zhu MY, Dilley G, Konick L, Overholser JC, Meltzer HY et al (2001). Effects of long-term cigarette smoking on the human locus coeruleus. Arch Gen Psychiatry 58: 821–827.
Kunduzova OR, Bianchi P, Parini A, Cambon C (2002). Hydrogen peroxide production by monoamine oxidase during ischemia/reperfusion. Eur J Pharmacol 448: 225–230.
Leroy C, Bragulat V, Berlin I, Gregoire MC, Bottlaender M, Roumenov D et al (2009). Cerebral monoamine oxidase A inhibition in tobacco smokers confirmed with PET and [11C]befloxatone. J Clin Psychopharmacol 29: 86–88.
Maertens GN, Cherepanov P, Engelman A (2006). Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J Cell Sci 119: 2563–2571.
Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A et al (2006). Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63: 1209–1216.
Meyer JH, Wilson AA, Sagrati S, Miler L, Rusjan P, Bloomfield PM et al (2009). Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psychiatry 66: 1304–1312.
Morilak DA, Frazer A (2004). Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int J Neuropsychopharmacol 7: 193–218.
Ou XM, Chen K, Shih JC (2006a). Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1. J Biol Chem 281: 21512–21525.
Ou XM, Chen K, Shih JC (2006b). Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc Natl Acad Sci USA 103: 10923–10928.
Ou XM, Lu D, Johnson C, Chen K, Youdim MB, Rajkowska G et al (2009a). Glyceraldehyde-3-phosphate dehydrogenase-monoamine oxidase B-mediated cell death-induced by ethanol is prevented by rasagiline and 1-R-aminoindan. Neurotox Res 16: 148–159.
Ou XM, Stockmeier CA, Meltzer HY, Overholser JC, Jurjus GJ, Dieter L et al (2009b). A novel role for glyceraldehyde-3-phosphate dehydrogenase and monoamine oxidase B cascade in ethanol-induced cellular damage. Biol Psychiatry 67: 855–863.
Ou XM, Storring JM, Kushwaha N, Albert PR (2001). Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene. J Biol Chem 276: 14299–14307.
Rajkowska G, Miguel-Hidalgo JJ, Dubey P, Stockmeier CA, Krishnan KR (2005). Prominent reduction in pyramidal neurons density in the orbitofrontal cortex of elderly depressed patients. Biol Psychiatry 58: 297–306.
Reilly JG, McTavish SF, Young AH (1997). Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J Psychopharmacol 11: 381–392.
Sacher J, Wilson AA, Houle S, Rusjan P, Hassan S, Bloomfield PM et al (2010). Elevated brain monoamine oxidase A binding in the early postpartum period. Arch Gen Psychiatry 67: 468–474.
Sanacora G (2008). New understanding of mechanisms of action of bipolar medications. J Clin Psychiatry 69 (Suppl 5): 22–27.
Schmidt HD, Duman RS (2007). The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18: 391–418.
Sherif F, Marcusson J, Oreland L (1991). Brain gamma-aminobutyrate transaminase and monoamine oxidase activities in suicide victims. Eur Arch Psychiatry Clin Neurosci 241: 139–144.
Shih JC (1991). Molecular basis of human MAO A and B. Neuropsychopharmacology 4: 1–7.
Shih JC, Chen K (1999). MAO-A and -B gene knock-out mice exhibit distinctly different behavior. Neurobiology (Bp) 7: 235–246.
Shih JC, Grimsby J, Chen K, Zhu QS (1993). Structure and promoter organization of the human monoamine oxidase A and B genes. J Psychiatry Neurosci 18: 25–32.
Stockmeier CA, Howley E, Shi X, Sobanska A, Clarke G, Friedman L et al (2009). Antagonist but not agonist labeling of serotonin-1A receptors is decreased in major depressive disorder. J Psychiatr Res 43: 887–894.
Tatsumi M, Groshan K, Blakely RD, Richelson E (1997). Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340: 249–258.
Thalmeier A, Dickmann M, Giegling I, Schneider B, A MH, Maurer K et al (2008). Gene expression profiling of post-mortem orbitofrontal cortex in violent suicide victims. Int J Neuropsychopharmacol 11: 217–228.
Youdim MB, Bakhle YS (2006). Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness. Br J Pharmacol 147 (Suppl 1): S287–S296.
Youdim MB, Edmondson D, Tipton KF (2006). The therapeutic potential of monoamine oxidase inhibitors. Nat Rev 7: 295–309.
Youdim MB, Fridkin M, Zheng H (2004). Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson's disease and other neurodegenerative diseases. J Neural Transm 111: 1455–1471.
Young SN, Smith SE, Pihl RO, Ervin FR (1985). Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (Berl) 87: 173–177.
Zhu QS, Chen K, Shih JC (1994). Bidirectional promoter of human monoamine oxidase A (MAO A) controlled by transcription factor Sp1. J Neurosci 14: 7393–7403.
Acknowledgements
This research was supported by Public Health Service Grants P20 RR 017701, MH67996, National Alliance for Research on Schizophrenia and Depression, the Canadian Institutes of Health Research, and an Intramural Research Support grant from the University of Mississippi Medical Center. We gratefully acknowledge the invaluable contributions made by the families consenting to donate brain tissue and to be interviewed. The kind assistance of the Cuyahoga County Coroner's office, Cleveland, Ohio, is also noted. We thank Dr Herbert Y Meltzer for psychiatric assessment assistance. Nicole Herbst, Timothy De Jong, Shawnnette Nelson, and Nicole Peak assisted with human tissues and obtaining written consent. Dr Gouri Mahajan, Chinelo Udemgba, and John Sullivan assisted with tissue preparation and western blot analyses.
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Dr Meyer has applied for a patent to apply MAO measures to diagnose or identify subtypes of MDD and he has had operating grant support/consultation with GlaxoSmithKline, BristolMyersSquibb, Lundbeck, SK Life Sciences, and Eli-Lilly. All other authors declare no conflict of interest.
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Johnson, S., Stockmeier, C., Meyer, J. et al. The Reduction of R1, a Novel Repressor Protein for Monoamine Oxidase A, in Major Depressive Disorder. Neuropsychopharmacol 36, 2139–2148 (2011). https://doi.org/10.1038/npp.2011.105
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DOI: https://doi.org/10.1038/npp.2011.105
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