Tryptophan Hydroxylase

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Victoria Arango - One of the best experts on this subject based on the ideXlab platform.

  • neuronal Tryptophan Hydroxylase expression in balb cj and c57bl 6j mice
    Journal of Neurochemistry, 2011
    Co-Authors: Helene Bach, Victoria Arango, John J Mann, Yungyu Huang, Sharlene Leong, Mark D Underwood
    Abstract:

    J. Neurochem. (2011) 118, 1067–1074. Abstract BALB/c is an inbred stress-sensitive mouse strain exhibiting low brain serotonin (5-HT) content and a 5-HT biosynthetic enzyme Tryptophan Hydroxylase (Tph2) variant reported to have lower catalytic activity compared with other inbred base strains. To evaluate other mechanisms that may explain low 5-HT, we compared BALB/cJ mice and a control inbred strain C57Bl/6J mice, for expression of Tph2 mRNA, TPH2 protein and regional levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Tph2 mRNA and TPH2 protein in brainstem dorsal raphe nuclei was assayed by in situ hybridization and immunocytochemistry respectively. 5-HT and 5-hydroxyindoleacetic acid were determined by HPLC. BALB/cJ mice had 20% less Tph2 mRNA and 28% fewer TPH2 immunolabeled neurons than C57Bl/6J mice (t = −2.59, p = 0.02). The largest difference in Tph2 transcript expression was in rostral dorsal raphe nuclei (t = 2.731, p = 0.008). 5-HT was 15% lower in the midbrain and 18% lower in the cerebral cortex of BALB/cJ compared with C57Bl/6J mice (p < 0.05). The behavioral differences in BALB/cJ mice relative to the C57Bl/6J strain may be due in part, to fewer 5-HT neurons and lower Tph2 gene expression resulting in less 5-HT neurotransmission. Future studies quantifying expression per neuron are needed to determine whether less expression is explained by fewer neurons or also less expression per neuron, or both.

  • genetic architecture of the human Tryptophan Hydroxylase 2 gene existence of neural isoforms and relevance for major depression
    Molecular Psychiatry, 2008
    Co-Authors: Fatemeh Haghighi, Victoria Arango, Helene Bachmizrachi, Yungyu Huang, Shundi Shi, Andrew J Dwork, Gorazd Rosoklija, Huitao Sheng, Irina Morozova, James J Russo
    Abstract:

    Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan Hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.

  • neuronal Tryptophan Hydroxylase mrna expression in the human dorsal and median raphe nuclei major depression and suicide
    Neuropsychopharmacology, 2006
    Co-Authors: Helene Bachmizrachi, Mark D Underwood, Suham Kassir, Mihran J Bakalian, Hadassah Tamir, John J Mann, Etienne Sibille, Victoria Arango
    Abstract:

    Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide

  • immobilization stress elevates Tryptophan Hydroxylase mrna and protein in the rat raphe nuclei
    Biological Psychiatry, 2004
    Co-Authors: Firas Chamas, Mark D Underwood, Victoria Arango, Lidia I Serova, Suham Kassir, John J Mann, Esther L Sabban
    Abstract:

    Abstract Background Stress triggers adaptive and maladaptive changes in the central nervous system, including activation of the hypothalamic–pituitary–adrenal axis, and can trigger mood disorders and posttraumatic stress disorder. We examined the effect of immobilization stress (IMO) on gene expression of Tryptophan Hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, and the role of cortisol in that response. Methods Regular and adrenalectomized Sprague-Dawley rats were exposed to various repetitions of IMO. Tryptophan Hydroxylase messenger ribonucleic acid (mRNA) was determined by competitive reverse transcriptase polymerase chain reaction, and TPH protein was examined by immunoblot and immunocytochemistry. Results Elevation of TPH mRNA by IMO was tissue-specific and dose-dependent. A single IMO elicited a threefold rise in TPH mRNA in median raphe nucleus (MRN), but repeated (3×) IMOs were needed for similar response in dorsal raphe nucleus (DRN). Repeated daily IMO, up to 7 days, triggered a robust induction (6–10-fold) in TPH mRNA, accompanied by corresponding rise in TPH protein levels in raphe nuclei but not in the pineal gland. The rise in TPH immunoreactivity was widespread throughout the DRN and MRN. Bilateral adrenalectomy did not prevent the IMO-triggered increase in TPH immunoreactive protein in the raphe nuclei. Conclusions This study reveals adrenal glucocorticoid–independent induction of TPH gene expression in raphe nuclei in response to immobilization stress.

John J Mann - One of the best experts on this subject based on the ideXlab platform.

  • neuronal Tryptophan Hydroxylase expression in balb cj and c57bl 6j mice
    Journal of Neurochemistry, 2011
    Co-Authors: Helene Bach, Victoria Arango, John J Mann, Yungyu Huang, Sharlene Leong, Mark D Underwood
    Abstract:

    J. Neurochem. (2011) 118, 1067–1074. Abstract BALB/c is an inbred stress-sensitive mouse strain exhibiting low brain serotonin (5-HT) content and a 5-HT biosynthetic enzyme Tryptophan Hydroxylase (Tph2) variant reported to have lower catalytic activity compared with other inbred base strains. To evaluate other mechanisms that may explain low 5-HT, we compared BALB/cJ mice and a control inbred strain C57Bl/6J mice, for expression of Tph2 mRNA, TPH2 protein and regional levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Tph2 mRNA and TPH2 protein in brainstem dorsal raphe nuclei was assayed by in situ hybridization and immunocytochemistry respectively. 5-HT and 5-hydroxyindoleacetic acid were determined by HPLC. BALB/cJ mice had 20% less Tph2 mRNA and 28% fewer TPH2 immunolabeled neurons than C57Bl/6J mice (t = −2.59, p = 0.02). The largest difference in Tph2 transcript expression was in rostral dorsal raphe nuclei (t = 2.731, p = 0.008). 5-HT was 15% lower in the midbrain and 18% lower in the cerebral cortex of BALB/cJ compared with C57Bl/6J mice (p < 0.05). The behavioral differences in BALB/cJ mice relative to the C57Bl/6J strain may be due in part, to fewer 5-HT neurons and lower Tph2 gene expression resulting in less 5-HT neurotransmission. Future studies quantifying expression per neuron are needed to determine whether less expression is explained by fewer neurons or also less expression per neuron, or both.

  • neuronal Tryptophan Hydroxylase mrna expression in the human dorsal and median raphe nuclei major depression and suicide
    Neuropsychopharmacology, 2006
    Co-Authors: Helene Bachmizrachi, Mark D Underwood, Suham Kassir, Mihran J Bakalian, Hadassah Tamir, John J Mann, Etienne Sibille, Victoria Arango
    Abstract:

    Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide

  • immobilization stress elevates Tryptophan Hydroxylase mrna and protein in the rat raphe nuclei
    Biological Psychiatry, 2004
    Co-Authors: Firas Chamas, Mark D Underwood, Victoria Arango, Lidia I Serova, Suham Kassir, John J Mann, Esther L Sabban
    Abstract:

    Abstract Background Stress triggers adaptive and maladaptive changes in the central nervous system, including activation of the hypothalamic–pituitary–adrenal axis, and can trigger mood disorders and posttraumatic stress disorder. We examined the effect of immobilization stress (IMO) on gene expression of Tryptophan Hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, and the role of cortisol in that response. Methods Regular and adrenalectomized Sprague-Dawley rats were exposed to various repetitions of IMO. Tryptophan Hydroxylase messenger ribonucleic acid (mRNA) was determined by competitive reverse transcriptase polymerase chain reaction, and TPH protein was examined by immunoblot and immunocytochemistry. Results Elevation of TPH mRNA by IMO was tissue-specific and dose-dependent. A single IMO elicited a threefold rise in TPH mRNA in median raphe nucleus (MRN), but repeated (3×) IMOs were needed for similar response in dorsal raphe nucleus (DRN). Repeated daily IMO, up to 7 days, triggered a robust induction (6–10-fold) in TPH mRNA, accompanied by corresponding rise in TPH protein levels in raphe nuclei but not in the pineal gland. The rise in TPH immunoreactivity was widespread throughout the DRN and MRN. Bilateral adrenalectomy did not prevent the IMO-triggered increase in TPH immunoreactive protein in the raphe nuclei. Conclusions This study reveals adrenal glucocorticoid–independent induction of TPH gene expression in raphe nuclei in response to immobilization stress.

  • aggression and anger related traits associated with a polymorphism of the Tryptophan Hydroxylase gene
    Biological Psychiatry, 1999
    Co-Authors: Stephen B Manuck, John J Mann, Robert E Ferrell, Janine D Flory, Karin M Dent, Matthew F Muldoon
    Abstract:

    Abstract Background: Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for Tryptophan Hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. Methods: Locally recruited men and women ( n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). Results: Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. Conclusions: Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

  • possible association of a polymorphism of the Tryptophan Hydroxylase gene with suicidal behavior in depressed patients
    American Journal of Psychiatry, 1997
    Co-Authors: John J Mann, David Goldman, David A Nielsen, Kevin M Malone, Joseph Erdos, Joel Gelernter
    Abstract:

    Objective: This study was designed to test the hypothesis that serotonin-system-related genes may be correlated with suicide risk. Method: Fifty-one unrelated Caucasian inpatients with major depression, with or without a history of suicidal acts, were genotyped for a biallelic polymorphism at the Tryptophan Hydroxylase locus. Results: The less common Tryptophan Hydroxylase U allele occurred with greater frequency in the patients who had attempted suicide. A logistic regression analysis confirmed an association between Tryptophan Hydroxylase genotype and lifetime history of suicide attempts. Conclusions: Serotonergic-system-related genes may influence the risk of suicide in persons with major depression. (Am J Psychiatry 1997; 154:1451‐1453)

Rosario Leopardi - One of the best experts on this subject based on the ideXlab platform.

  • the Tryptophan Hydroxylase tph 2 gene unlike tph 1 exhibits no association with stress induced depression
    Journal of Affective Disorders, 2008
    Co-Authors: R Z Gizatullin, Ghazal Zaboli, Erik G Jonsson, Marie Asberg, Rosario Leopardi
    Abstract:

    Abstract Background Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depression (MD). Tryptophan Hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), and might be related to the pathogenesis of MD. Two isoforms are known, TPH-1 and TPH-2 . Their association with MD is still debated. Methods A case-control design was used for candidate gene-disease association in 194 patients with stress-induced MD, and 246 healthy controls, all North European Caucasians. Five TPH-2 polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. Results Neither single marker nor haplotype-based analyses showed significant associations between TPH-2 and MD. Limitations The interpretations are limited by the restricted population size. Conclusions There was no association between TPH-2 gene variants and MD in the same population that had shown a strong association with TPH-1 . Hence, the results suggest that in this particular group of stress-induced depression patients TPH-1 appears to be more relevant to MD pathogenesis than TPH-2 .

  • haplotype analysis reveals Tryptophan Hydroxylase tph 1 gene variants associated with major depression
    Biological Psychiatry, 2006
    Co-Authors: R Z Gizatullin, Ghazal Zaboli, Erik G Jonsson, Marie Asberg, Rosario Leopardi
    Abstract:

    Background Tryptophan Hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT) and might be related to the pathogenesis of major depression (MD). Two isoforms are known, TPH-1 and TPH-2. Tryptophan Hydroxylase-1 association with MD is still debated. Methods A single nucleotide polymorphism (SNP) screening strategy was used to define TPH-1 haplotypes spanning over 23 kilobase (kb) of the 29 kb gene length. Genotyping was performed in 228 MD patients and 253 healthy control subjects. Results Six SNPs were found at linkage disequilibrium in both patients and control subjects, suggesting a haplotype block structure. Single marker association analyses showed only one SNP significantly associated with MD. Several haplotypes were associated with MD. When all six locus haplotypes were divided into two groups, above or below a 5% threshold, the compound haplotype group below a 5% frequency resulted as associated with the disease (31.6% vs. 18.0% in control subjects, p −5 ). A "sliding window" analysis attributed the strongest disease association to a haplotype configuration localized between introns 7 and 8 ( p −5 ). Conclusions Haplotype analysis indicates that TPH-1 associates with MD. The most common TPH-1 variants appear to carry no risk, while some of the less frequent variants might contribute to genetic predisposition to MD.

Xiaodong Zhang - One of the best experts on this subject based on the ideXlab platform.

  • a functional alternative splicing mutation in human Tryptophan Hydroxylase 2
    Molecular Psychiatry, 2011
    Co-Authors: Tatyana D. Sotnikova, Xiaodong Zhang, Peter J Nicholls, Gonzalo Laje, Raul R Gainetdinov, Paul R Albert, Grazyna Rajkowska
    Abstract:

    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.

  • a regulatory domain in the n terminus of Tryptophan Hydroxylase 2 controls enzyme expression
    Journal of Biological Chemistry, 2008
    Co-Authors: Karen L Murphy, Raul R Gainetdinov, Xiaodong Zhang, Jean-martin Beaulieu
    Abstract:

    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.

  • Loss-of-function mutation in Tryptophan Hydroxylase-2 identified in unipolar major depression.
    Neuron, 2005
    Co-Authors: Xiaodong Zhang, Jean-martin Beaulieu, Lauranell H. Burch, Tatyana D. Sotnikova, Redford B Williams, David A Schwartz, K. Ranga Rama Krishnan
    Abstract:

    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.

  • Tryptophan Hydroxylase 2 controls brain serotonin synthesis
    Science, 2004
    Co-Authors: Xiaodong Zhang, Jean-martin Beaulieu, Tatyana D. Sotnikova, Raul R Gainetdinov
    Abstract:

    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.

Mark D Underwood - One of the best experts on this subject based on the ideXlab platform.

  • neuronal Tryptophan Hydroxylase expression in balb cj and c57bl 6j mice
    Journal of Neurochemistry, 2011
    Co-Authors: Helene Bach, Victoria Arango, John J Mann, Yungyu Huang, Sharlene Leong, Mark D Underwood
    Abstract:

    J. Neurochem. (2011) 118, 1067–1074. Abstract BALB/c is an inbred stress-sensitive mouse strain exhibiting low brain serotonin (5-HT) content and a 5-HT biosynthetic enzyme Tryptophan Hydroxylase (Tph2) variant reported to have lower catalytic activity compared with other inbred base strains. To evaluate other mechanisms that may explain low 5-HT, we compared BALB/cJ mice and a control inbred strain C57Bl/6J mice, for expression of Tph2 mRNA, TPH2 protein and regional levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Tph2 mRNA and TPH2 protein in brainstem dorsal raphe nuclei was assayed by in situ hybridization and immunocytochemistry respectively. 5-HT and 5-hydroxyindoleacetic acid were determined by HPLC. BALB/cJ mice had 20% less Tph2 mRNA and 28% fewer TPH2 immunolabeled neurons than C57Bl/6J mice (t = −2.59, p = 0.02). The largest difference in Tph2 transcript expression was in rostral dorsal raphe nuclei (t = 2.731, p = 0.008). 5-HT was 15% lower in the midbrain and 18% lower in the cerebral cortex of BALB/cJ compared with C57Bl/6J mice (p < 0.05). The behavioral differences in BALB/cJ mice relative to the C57Bl/6J strain may be due in part, to fewer 5-HT neurons and lower Tph2 gene expression resulting in less 5-HT neurotransmission. Future studies quantifying expression per neuron are needed to determine whether less expression is explained by fewer neurons or also less expression per neuron, or both.

  • neuronal Tryptophan Hydroxylase mrna expression in the human dorsal and median raphe nuclei major depression and suicide
    Neuropsychopharmacology, 2006
    Co-Authors: Helene Bachmizrachi, Mark D Underwood, Suham Kassir, Mihran J Bakalian, Hadassah Tamir, John J Mann, Etienne Sibille, Victoria Arango
    Abstract:

    Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide

  • immobilization stress elevates Tryptophan Hydroxylase mrna and protein in the rat raphe nuclei
    Biological Psychiatry, 2004
    Co-Authors: Firas Chamas, Mark D Underwood, Victoria Arango, Lidia I Serova, Suham Kassir, John J Mann, Esther L Sabban
    Abstract:

    Abstract Background Stress triggers adaptive and maladaptive changes in the central nervous system, including activation of the hypothalamic–pituitary–adrenal axis, and can trigger mood disorders and posttraumatic stress disorder. We examined the effect of immobilization stress (IMO) on gene expression of Tryptophan Hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, and the role of cortisol in that response. Methods Regular and adrenalectomized Sprague-Dawley rats were exposed to various repetitions of IMO. Tryptophan Hydroxylase messenger ribonucleic acid (mRNA) was determined by competitive reverse transcriptase polymerase chain reaction, and TPH protein was examined by immunoblot and immunocytochemistry. Results Elevation of TPH mRNA by IMO was tissue-specific and dose-dependent. A single IMO elicited a threefold rise in TPH mRNA in median raphe nucleus (MRN), but repeated (3×) IMOs were needed for similar response in dorsal raphe nucleus (DRN). Repeated daily IMO, up to 7 days, triggered a robust induction (6–10-fold) in TPH mRNA, accompanied by corresponding rise in TPH protein levels in raphe nuclei but not in the pineal gland. The rise in TPH immunoreactivity was widespread throughout the DRN and MRN. Bilateral adrenalectomy did not prevent the IMO-triggered increase in TPH immunoreactive protein in the raphe nuclei. Conclusions This study reveals adrenal glucocorticoid–independent induction of TPH gene expression in raphe nuclei in response to immobilization stress.

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