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Alexander V. Kulikov - One of the best experts on this subject based on the ideXlab platform.
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Tryptophan Hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models
Expert opinion on therapeutic targets, 2019Co-Authors: Elizabeth A. Kulikova, Alexander V. KulikovAbstract:Introduction: Tryptophan Hydroxylase 2 (TPH2) is the key, rate-limiting enzyme of serotonin (5-HT) synthesis in the brain. Some polymorphic variants of the human Tph2 gene are associated with psychiatric disorders. Area covered: This review focuses on the mechanisms underlying the association between the TPH2 activity and behavioral disturbances in models of psychiatric disorders. Specifically, it discusses: 1) genetic and posttranslational mechanisms defining the TPH2 activity, 2) behavioral effects of knockout and loss-of-function mutations in the mouse Tph2 gene, 3) pharmacological inhibition and the activation of the TPH2 activity and 4) alterations in the brain TPH2 activity in animal models of psychiatric disorders. We show the dual role of the TPH2 activity: both deficit and excess of the TPH2 activity cause significant behavioral disturbances in animal models of depression, anxiety, aggression, obsessive-compulsive disorders, schizophrenia, and catalepsy. Expert opinion: Pharmacological chaperones correcting the structure of the TPH2 molecule are promising tools for treatment of some hereditary psychiatric disorders caused by loss-of-function mutations in the human Tph2 gene; while some stress-induced affective disorders, associated with the elevated TPH2 activity, may be effectively treated by TPH2 inhibitors. This dual role of TPH2 should be taken into consideration during therapy of psychiatric disorders.
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C1473G polymorphism in mouse Tryptophan Hydroxylase-2 gene in the regulation of the reaction to emotional stress.
Neuroscience letters, 2017Co-Authors: E.y. Bazhenova, Daria V. Bazovkina, Elizabeth A. Kulikova, D. V. Fursenko, Nikita V. Khotskin, Daria V. Lichman, Alexander V. KulikovAbstract:Abstract Neurotransmitter serotonin (5-HT) is involved in the regulation of stress response. Tryptophan Hydroxylase-2 (TPH2) is the key enzyme of serotonin (5-HT) synthesis in the brain. C1473G polymorphism in Tph2 gene is the main factor defining the enzyme activity in the brain of laboratory mice. The effect of interaction between C1473G polymorphism and 30 min restriction stress on the behavior in the open field test, c-Fos gene expression and 5-HT metabolism in the brain in adult male of B6-1473C and B6-1473G congenic mouse lines with high and low TPH2 activity was investigated. A significant effect of genotype x stress interaction on c-Fos mRNA in the hypothalamus (F 1,21 = 10.66, p 1,21 = 9.18, p c-Fos mRNA in these structures is more intensive in B6-1473G than in B6-1473C mice. A marked effect of genotype x stress interaction on 5-HT level in the cortex (F 1,18 = 9.38, p 1,18 = 9.01, p
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The C1473G polymorphism in the Tryptophan Hydroxylase-2 gene: involvement in ethanol-related behavior in mice.
Neuroscience letters, 2015Co-Authors: D. V. Bazovkina, Daria V. Lichman, Alexander V. KulikovAbstract:Abstract Tryptophan Hydroxylase-2 ( Tph2 ) is the rate limiting enzyme of serotonin synthesis in the brain. The functional (C1473G) polymorphism in the mouse Tph2 gene affecting the enzymatic activity was suspected to be involved in behavioral actions of ethanol (EtOH). Congenic B6–1473C (C/C) and B6–1473G (G/G) lines bred from C57BL/6 mice were not different in EtOH-induced sleep time and hypothermia. B6–1473C mice displayed increased EtOH preference on the second and third days compared to that of the first day, but no differences in this parameter was found across genotypes. Both lines demonstrated the same responsiveness to hypothermic and hypnotic effect of acute EtOH treatment after repeated alcohol exposure. However, acute EtOH administration led to reduction of locomotor activity in B6–1473C, but not in B6–1473G animals and to increase of time spent in the center of open-field arena in B6–1473G, but not in B6–1473C mice. Thus, the present study indicates the involvement of C1473G polymorphism in mTph2 gene in the regulation of EtOH-induced effects on locomotor activity and anxiety-like behavior in mice.
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Tryptophan Hydroxylase 2 in seasonal affective disorder: underestimated perspectives?
Reviews in the neurosciences, 2015Co-Authors: Alexander V. Kulikov, Nina K. PopovaAbstract:Seasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan Hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human TPH2 gene expression and the risk of affective disorder, application of Tryptophan to SAD treatment and the animal models of SAD. The main conclusions of this review are as follows: (i) the brain 5-HT deficiency contributes to the mechanism underlying SAD, (ii) TPH2 is involved in the regulation of some kinds of genetically defined affective disorders and (iii) the activation of 5-HT synthesis with exogenous l-Tryptophan alone or in combination with light therapy could be effective in SAD treatment. The synergic effect of these combined treatments will have several advantages compared to light or Tryptophan therapy alone. First, it is effective in the treatment of patients resistant to light therapy. Secondly, l-Tryptophan treatment prolongs the antidepressant effect of light therapy.
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Targeting Tryptophan Hydroxylase 2 in affective disorder.
Expert opinion on therapeutic targets, 2010Co-Authors: Nina K. Popova, Alexander V. KulikovAbstract:Importance of the field: Serotonin (5-HT) has been implicated in several psychiatric disorders including schizophrenia, depressive disorder and suicide. The key and rate limiting enzyme of 5-HT synthesis is Tryptophan Hydroxylase 2 (TPH2). Areas covered in this review: The association between TPH2 and affective disorders as well as future vistas of its potential clinical targeting: i) TPH2 in the regulation of 5-HT-dependent behavior, ii) TPH2 gene polymorphism and human behavior, iii) TPH2 and sensitivity to antidepressants and iv) effect of dietary Tryptophan manipulation on affective behavior are described. What the reader will gain: The main conclusions of the review are: i) there is an association between TPH2 and genetically defined behavioral variations, ii) the haplotypes, including some human TPH2 gene SNPs, can predict the risk of affective disorders and the sensitivity to antidepressant therapeutics, iii) mutations decreasing TPH2 activity produce negative effects on behavior and, possibly, on ...
Jan Haavik - One of the best experts on this subject based on the ideXlab platform.
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Functional properties of missense variants of human Tryptophan Hydroxylase 2.
Human mutation, 2009Co-Authors: Jeffrey A. Mckinney, Ingeborg Winge, Per M. Knappskog, Banu Turel, Jan HaavikAbstract:Tryptophan Hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the nervous system. Several variants of human TPH2 have been reported to be associated with a spectrum of neuropsychiatric disorders such as unipolar major depression, bipolar disorder, suicidality, and attention-deficit/hyperactivity disorder (ADHD). We used three different expression systems: rabbit reticulocyte lysate, Escherichia coli, and human embryonic kidney cells, to identify functional effects of all human TPH2 missense variants reported to date. The properties of mutants affecting the regulatory domain, that is, p.Leu36Val, p.Leu36Pro, p.Ser41Tyr, and p.Arg55Cys, were indistinguishable from the wild-type (WT). Moderate loss-of-function effects were observed for mutants in the catalytic and oligomerization domains, that is, p.Pro206Ser, p.Ala328Val, p.Arg441His, and p.Asp479Glu, which were manifested via stability and solubility effects, whereas p.Arg303Trp had severely reduced solubility and was completely inactive. All variants were tested as substrates for protein kinase A and were found to have similar phosphorylation stoichiometries. A standardized assay protocol as described here for activity and solubility screening should also be useful for determining properties of other TPH2 variants that will be discovered in the future. Hum Mutat 30:1–8, 2009. © 2009 Wiley-Liss, Inc.
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a loss of function mutation in Tryptophan Hydroxylase 2 segregating with attention deficit hyperactivity disorder
Molecular Psychiatry, 2008Co-Authors: Anne Halmøy, M. Dramsdahl, Ingeborg Winge, Per M. Knappskog, Stefan Johansson, Jeffrey Mckinney, Jan HaavikAbstract:A loss-of-function mutation in Tryptophan Hydroxylase 2 segregating with attention-deficit/hyperactivity disorder
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A loss-of-function mutation in Tryptophan Hydroxylase 2 segregating with attention-deficit/hyperactivity disorder.
Molecular Psychiatry, 2008Co-Authors: Jeffrey A. Mckinney, Anne Halmøy, M. Dramsdahl, Ingeborg Winge, Per M. Knappskog, Stefan Johansson, Jan HaavikAbstract:A loss-of-function mutation in Tryptophan Hydroxylase 2 segregating with attention-deficit/hyperactivity disorder
Xiaodong Zhang - One of the best experts on this subject based on the ideXlab platform.
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a functional alternative splicing mutation in human Tryptophan Hydroxylase 2
Molecular Psychiatry, 2011Co-Authors: Tatyana D. Sotnikova, Xiaodong Zhang, Peter J Nicholls, Gonzalo Laje, Raul R Gainetdinov, Paul R Albert, Grazyna RajkowskaAbstract:The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The Tryptophan Hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.
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a regulatory domain in the n terminus of Tryptophan Hydroxylase 2 controls enzyme expression
Journal of Biological Chemistry, 2008Co-Authors: Karen L Murphy, Jean-martin Beaulieu, Xiaodong Zhang, Raul R Gainetdinov, Marc G CaronAbstract:Abstract Serotonin is involved in a variety of physiological processes in the central nervous system and the periphery. As the rate-limiting enzyme in serotonin synthesis, Tryptophan Hydroxylase plays an important role in modulating these processes. Of the two variants of Tryptophan Hydroxylase, Tryptophan Hydroxylase 2 (TPH2) is expressed predominantly in the central nervous system, whereas Tryptophan Hydroxylase 1 (TPH1) is expressed mostly in peripheral tissues. Although the two enzymes share considerable sequence homology, the regulatory domain of TPH2 contains an additional 41 amino acids at the N terminus that TPH1 lacks. Here we show that the extended TPH2 N-terminal domain contains a unique sequence involved in the regulation of enzyme expression. When expressed in cultured mammalian cells, TPH2 is synthesized less efficiently and is also less stable than TPH1. Removal of the unique portion of the N terminus of TPH2 results in expression of the enzyme at a level similar to that of TPH1, whereas protein chimeras containing this fragment are expressed at lower levels than their wild-type counterparts. We identify a region centered on amino acids 10–20 that mediates the bulk of this effect. We also demonstrate that phosphorylation of serine 19, a protein kinase A consensus site located in this N-terminal domain, results in increased TPH2 stability and consequent increases in enzyme output in cell culture systems. Because this domain is unique to TPH2, these data provide evidence for selective regulation of brain serotonin synthesis.
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Visions & Reflections Functional polymorphisms of the brain serotonin synthesizing enzyme Tryptophan Hydroxylase-2
2006Co-Authors: Xiaodong Zhang, R. R. Gainetdinov, M. G. CaronAbstract:Many neuropsychiatric disorders are consid- ered to be related to the dysregulation of brain serotoner- gic neurotransmission. Tryptophan Hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain sero- tonin synthesis. There is growing genetic evidence for the possible involvement of TPH2 in serotonin-related neu-
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Loss-of-function mutation in Tryptophan Hydroxylase-2 identified in unipolar major depression.
Neuron, 2005Co-Authors: Xiaodong Zhang, Jean-martin Beaulieu, Lauranell H. Burch, K. Ranga Rama Krishnan, Tatyana D. Sotnikova, Redford B Williams, David A Schwartz, Marc G CaronAbstract:Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human Tryptophan Hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in ∼80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.
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Tryptophan Hydroxylase 2 controls brain serotonin synthesis
Science, 2004Co-Authors: Xiaodong Zhang, Jean-martin Beaulieu, Tatyana D. Sotnikova, Raul R Gainetdinov, Marc G CaronAbstract:Dysregulation of brain serotonin contributes to many psychiatric disorders. Tryptophan Hydroxylase-2 (Tph2), rather than Tph1, is preferentially expressed in the brain. We report a functional (C1473G) single-nucleotide polymorphism in mouse Tph2 that results in the substitution of Pro447 with Arg447 and leads to decreased serotonin levels in PC12 cells. Moreover, in BALB/cJ and DBA/2 mice that are homozygous for the 1473G allele, brain serotonin tissue content and synthesis are reduced in comparison to C57Bl/6 and 129X1/SvJ mice that are homozygous for the 1473C allele. Our data provide direct evidence for a fundamental role of Tph2 in brain serotonin synthesis.
Nina K. Popova - One of the best experts on this subject based on the ideXlab platform.
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Tryptophan Hydroxylase 2 in seasonal affective disorder: underestimated perspectives?
Reviews in the neurosciences, 2015Co-Authors: Alexander V. Kulikov, Nina K. PopovaAbstract:Seasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan Hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human TPH2 gene expression and the risk of affective disorder, application of Tryptophan to SAD treatment and the animal models of SAD. The main conclusions of this review are as follows: (i) the brain 5-HT deficiency contributes to the mechanism underlying SAD, (ii) TPH2 is involved in the regulation of some kinds of genetically defined affective disorders and (iii) the activation of 5-HT synthesis with exogenous l-Tryptophan alone or in combination with light therapy could be effective in SAD treatment. The synergic effect of these combined treatments will have several advantages compared to light or Tryptophan therapy alone. First, it is effective in the treatment of patients resistant to light therapy. Secondly, l-Tryptophan treatment prolongs the antidepressant effect of light therapy.
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Targeting Tryptophan Hydroxylase 2 in affective disorder.
Expert opinion on therapeutic targets, 2010Co-Authors: Nina K. Popova, Alexander V. KulikovAbstract:Importance of the field: Serotonin (5-HT) has been implicated in several psychiatric disorders including schizophrenia, depressive disorder and suicide. The key and rate limiting enzyme of 5-HT synthesis is Tryptophan Hydroxylase 2 (TPH2). Areas covered in this review: The association between TPH2 and affective disorders as well as future vistas of its potential clinical targeting: i) TPH2 in the regulation of 5-HT-dependent behavior, ii) TPH2 gene polymorphism and human behavior, iii) TPH2 and sensitivity to antidepressants and iv) effect of dietary Tryptophan manipulation on affective behavior are described. What the reader will gain: The main conclusions of the review are: i) there is an association between TPH2 and genetically defined behavioral variations, ii) the haplotypes, including some human TPH2 gene SNPs, can predict the risk of affective disorders and the sensitivity to antidepressant therapeutics, iii) mutations decreasing TPH2 activity produce negative effects on behavior and, possibly, on ...
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Distribution of the C1473G polymorphism in Tryptophan Hydroxylase 2 gene in laboratory and wild mice
Genes brain and behavior, 2010Co-Authors: D. V. Osipova, Alexander V. Kulikov, Kazuyuki Mekada, Atsushi Yoshiki, Mikhail P. Moshkin, E. V. Kotenkova, Nina K. PopovaAbstract:The neurotransmitter serotonin is implicated in the regulation of various forms of behavior, including aggression, sexual behavior and stress response. The rate of brain serotonin synthesis is determined by the activity of neuronal-specific enzyme Tryptophan Hydroxylase 2. The missense C1473G substitution in mouse Tryptophan Hydroxylase 2 gene has been shown to lower the enzyme activity and brain serotonin level. Here, the C1473G polymorphism was investigated in 84 common laboratory inbred strains, 39 inbred and semi-inbred strains derived from wild ancestors (mostly from Eurasia) and in 75 wild mice trapped in different locations in Russia and Armenia. Among all the classical inbred strains studied, only substrains of BALB/c, A and DBA, as well as the IITES/Nga and NZW/NSlc strains were homozygous for the 1473G allele. In contrast to laboratory strains, the 1473G allele was not present in any of the samples from wild and wild-derived mice, although the wild mice varied substantially in the C1477T neutral substitution closely linked to the C1473G polymorphism. According to these results, the frequency of the 1473G allele in natural populations does not exceed 0.5%, and the C1473G polymorphism is in fact a rare mutation that is possibly eliminated by the forces of natural selection.
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C1473G polymorphism in mouse tph2 gene is linked to Tryptophan Hydroxylase-2 activity in the brain, intermale aggression, and depressive-like behavior in the forced swim test.
Journal of neuroscience research, 2009Co-Authors: D. V. Osipova, Alexander V. Kulikov, Nina K. PopovaAbstract:Tryptophan Hydroxylase-2 (TPH2) is the rate-limiting enzyme of brain serotonin synthesis. The C1473G polymorphism in the mouse Tryptophan Hydroxylase-2 gene affects the enzyme's activity. In the present study, we investigated the linkage between the C1473G polymorphism, enzyme activity in the brain, and behavior in the forced swim, intermale aggression, and open field tests using mice of the C57BL/6 (C/C) and CC57BR/Mv (G/G) strains and the B6-1473C (C/C) and B6-1473G (G/G) lines created by three successive backcrossings on C57BL/6. Mice of the CC57BR/Mv strain had decreased brain enzyme activity, aggression intensity, and immobility in the forced swim test, but increased locomotor activity and time spent in the central part of the open field arena compared with animals of the C57BL/6 strain. Mice of the B6-1473G line homozygous for the 1473G allele had lower TPH2 activity in the brain, aggression intensity, and immobility time in the forced swim test compared with animals of the B6-1473C line homozygous for the 1473C allele. No differences were found between the B6-1473G and B6-1473C mice in locomotor activity and time spent in the central part of the arena in the open field test. Thus, the C1473G polymorphism is involved in the determination of TPH2 activity and is linked to aggression intensity and forced-swim immobility in mice. At the same time, the polymorphism does not affect locomotion and anxiety-related behavior in the open field test. The B6-1473C and B6-1473G mice represent a valuable experimental model for investigating molecular mechanisms of serotonin-related behavior.
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The C1473G polymorphism in gene tph2 is the main factor mediating the genetically defined variability of Tryptophan Hydroxylase-2 activity in the mouse brain
Genetika, 2007Co-Authors: Alexander V. Kulikov, D. V. Osipova, Nina K. PopovaAbstract:Brain neurotransmitter serotonin is involved in the regulation of many physiological functions and types of behavior. The key enzyme of serotonin synthesis in the brain is Tryptophan Hydroxylase-2 (TPH-2). Linkage between the C1473G polymorphism in gene tph2 causing the replacement of Pro447 by Arg447 in TPH-2 molecule and enzyme activity in the mouse brain of 10 inbred strains was found. Association of the polymorphism with the TPH-2 activity in the brain of F2 hybrids between strains C57BL/6 and CC57BR was shown. The results indicate that the C1473G polymorphism in gene tph2 is the main factor determining the genetically defined variability of enzyme activity in the mouse brain.
Tomas Furmark - One of the best experts on this subject based on the ideXlab platform.
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Serotonin Synthesis Rate and the Tryptophan Hydroxylase-2 G-703T Polymorphism in Social Anxiety Disorder
Biological Psychiatry, 2014Co-Authors: Iman Alaie, Andreas Frick, Ina Marteinsdottir, Per Hartvig, Maria Tillfors, Elias Eriksson, Mats Fredrikson, Tomas FurmarkAbstract:Serotonin Synthesis Rate and the Tryptophan Hydroxylase-2 G-703T Polymorphism in Social Anxiety Disorder
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Effects of serotonin transporter and Tryptophan Hydroxylase-2 gene variation on the response to cognitive-bahavior therapy in patients with social anxiety disorder
2010Co-Authors: Tomas Furmark, Elias Eriksson, Per Carlbring, Sara Hammer, Ika Wahlgren, Lisa Ekselius, Gerhard AnderssonAbstract:Effects of serotonin transporter and Tryptophan Hydroxylase-2 gene variation on the response to cognitive-bahavior therapy in patients with social anxiety disorder
