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Gilles de la Tourette’s syndrome
Published in David Enoch, Basant K. Puri, Hadrian Ball, Uncommon Psychiatric Syndromes, 2020
David Enoch, Basant K. Puri, Hadrian Ball
Turning to the biosynthesis of serotonin, Mössner et al. (2007) have studied TPH2 in Tourette syndrome; this gene encodes the enzyme tryptophan hydroxylase 2, which is associated with serotonin biosynthesis in the brain and has chromosomal location 12q21. In this German study, 98 Tourette syndrome patients were compared with 178 controls. The single-nucleotide polymorphism (SNP) rs4565946 showed an association with Tourette syndrome; no such association was found for the other SNP studied, namely rs4570625 (which the authors may have chosen because of previous functional neuroimaging study findings).
Melatonin: A “Guardian” of the Genome and Cellular Integrity for Prevention of Photocarcinogenesis
Published in Andreia Ascenso, Sandra Simões, Helena Ribeiro, Carrier-Mediated Dermal Delivery, 2017
Patricia Manteigas, Andreia Ascenso
The melatonin-biosynthesis pathway in skin, similar to what happens in other organs, is divided into four stages (Fig. 2.2), initiated by the uptake of the essential amino acid L-tryptophan by pineal parenchymal cells [6,31,36]. After this, L-tryptophan is converted to another amino acid, 5-hydroxytryp- tophan due the action of tryptophan hydroxylase enzyme (TPH), which is dependent on (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4) [37]. There are two isoforms of tryptophan hydroxylase identified as TPH1 and TPH2. The first one is expressed in many peripheral tissues, including the skin, whereas TPH2 is expressed predomi- nantly in the central nervous system [38]. Thus, TPH1 is the responsible enzyme for the production of melatonin at skin level [33]. The second step of melatonin synthesis involves the decarboxylation of 5-hydroxytryptophan to serotonin by the aromatic amino acid decarboxylase enzyme (AAD). In the third step, serotonin is acetylated to N-acetylserotonin by arylalkylamine N-acetyltransferase (AANAT). Further, it is methyl- ated to melatonin via hydroxyindole-0-methyltransferase (HIOMT).
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
The rate-limiting step in the overall conversion of tryptophan to serotonin is the first step that is catalyzed by TPH (Figure 16.9) and results in the conversion of tryptophan to 5-hydroxytryptophan (5-HTP). Like tyrosine hydroxylase, tryptophan hydroxylase is a cytoplasmic mixed-function oxidase that requires molecular oxygen and a reduced pteridine as cofactors. It should also be noted that a membrane-associated form of tryptophan hydroxylase has been found, indicating that some of the enzyme may be membrane bound. Two isoforms of tryptophan hydroxylase (tryptophan hydroxylase-1 and tryptophan hydroxylase-2) have been identified. Tryptophan hydroxylase-2 (TPH2) is the one that is expressed primarily in the brain.107 Polymorphisms (alterations) in the gene that codes for TPH2 may be associated with altered susceptibility to affective disorders (e.g., depression) and one’s responsiveness to antidepressants.1 Various inhibitors of tryptophan hydroxylase have been identified, the best known of which is parachlorophenylalanine (PCPA), which has been used experimentally to study the function of 5-HT.
Targeted sequencing approach: Comprehensive analysis of DNA methylation and gene expression across blood and brain regions in suicide victims
Published in The World Journal of Biological Psychiatry, 2023
Katarina Kouter, Tomaž Zupanc, Alja Videtič Paska
TPH2 is a brain-specific rate-limiting enzyme isoform, involved in serotonin synthesis (Walther et al. 2003). The TPH2 gene does not contain a CGI, so we amplified the sequence before the start of the coding sequence, which also contains sites for transcription factor binding (neuron-restrictive silencer factor (NRSF) and CCCTC-binding factor (CTCF)), which can act as a switch for gene expression (Patel et al. 2007; Chen and Miller 2012). Highest number of significant DMCs were observed in the hippocampus. Our amplicon included a CpG (chr12:72332657) within the transcription factor binding site, which was statistically significant in BA46 and blood (hypomethylated) and in hippocampus (hypermethylated). Comparing mean methylation levels per amplicon, no tissue region remained significant after multiple testing correction.
Tryptophan hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models
Published in Expert Opinion on Therapeutic Targets, 2019
Elizabeth A. Kulikova, Alexander V. Kulikov
Experimental studies discussed in this review confirm and complement clinical data on association between TPH2 and psychiatric disorders. TPH2 is mandatory for 5-HT synthesis in the brain, and it is expressed specifically in the serotoninergic neurons [7]. The mice with Tph2 gene knockout demonstrate almost total absence of 5-HT in the brain [24–26]. Loss-of-function mutations in the Tph2 gene are rare in the human [27,50] and natural mice [62] populations. This can be considered as an indirect evidence for an adaptive impact of the ‘normal’ TPH2 activity.A ‘normal’ (wild-type) TPH2 activity is mandatory for adaptive behavior of mice and rats, while genetic decrease in the TPH2 activity can cause various deviations from it. This conclusion agrees with numerous clinical observations of association between some polymorphisms in the hTph2 gene and the risk of psychiatric disorders as well as resistance to psychotropic drugs [see reviews 27,28,30,31,32]. The R439H loss-of-function substitution in mTph2 gene induces behavioral alterations, such as depressive- and OCD-like behaviors [51–53]. This substitution is homologous of the rare R441H mutation in the hTph2 gene that is associated with grave and resistant to antidepressant treatment unipolar depression [50].Stress that usually causes affective disorders (anxiety and depression) increases the TPH2 activity or expression in the rat brain [30,107–111]. This stress-induced increase in the TPH2 activity can be normalized using antidepressant drugs [86]. These results agree with that of rare postmortem studies demonstrate the increase in hTph2 gene expression in the dorsal raphe nuclei in suicides [34,35,91–96].
Decreased tryptophan hydroxylase 2 mRNA and protein expression, decreased brain serotonin concentrations, and anxiety-like behavioral changes in a rat model of simulated transport stress
Published in Stress, 2019
Lili Wang, Deping Han, Peng Yin, Kedao Teng, Jianqin Xu, Yunfei Ma
TPH2 is an important enzyme that catalyzes the first rate-limiting step in 5-hydroxytryptamine synthesis, which might be the key regulator of the concentration of 5-hydroxytryptamine in the rat brain. Our results showed that TPH2 mRNA and protein expression levels were significantly lower in the brain of the TS rats, consistent with the finding that transport stress decreased tissue concentrations of 5-hydroxytryptamine.