Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lithium inhibits inositol monophosphatase at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium's therapeutic efficacy in bipolar disorder. We have employed adult rat cortical slices as a model to investigate the gene regulatory consequences of inositol depletion effected by lithium using cytidine diphosphoryl-diacylglycerol as a functionally relevant biochemical marker to define treatment conditions. Genes coding for the neuropeptide hormone pituitary adenylate cyclase activating polypeptide (PACAP) and the enzyme that processes PACAP's precursor to the mature form, peptidylglycine alpha-amidating monooxygenase, were upregulated by inositol depletion. Previous work has shown that PACAP can increase tyrosine hydroxylase (TH) activity and dopamine release, and we found that the gene for GTP cyclohydrolase, which effectively regulates TH through synthesis of tetrahydrobiopterin, was also upregulated by inositol depletion. We propose that modulation of brain PACAP signaling might represent a new opportunity in the treatment of bipolar disorder.
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PMID:Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex. 1579 48

Estrogen is likely involved in the gender specific differences in coping with stress. Activation of catecholamine (CA) biosynthetic enzyme gene expression in central and peripheral CA systems plays a key role in response to stress and in regulation of the cardiovascular system. Here we examined whether estradiol can modulate response of hypothalamic-pituitary-adrenal axis (HPA), gene expression of enzymes related to CA biosynthesis in several noradrenergic locations, tetrahydrobiopterin (BH4) concentration and blood pressure (BP) in response to immobilization stress (IMO) of ovariectomized female rats. Rats were injected with 25 mug/kg estradiol benzoate (EB) or sesame oil once daily for 16 days and subsequently exposed to two hours of IMO. The IMO triggered elevation in plasma ACTH was lessened in EB-pretreated animals. However, estradiol did not alter the IMO-elicited rise of tyrosine hydroxylase mRNA levels in adrenal medulla (AM) and in the nucleus of solitary track (NTS) compared with controls. The response of GTP cyclohydrolase I (GTPCH) mRNA in AM to IMO was also similar in both groups. Several responses to IMO in EB-treated rats were reversed. Instead of IMO-elicited elevation in dopamine beta-hydroxylase mRNA levels in the locus coeruleus, GTPCH mRNA and BH4 levels in the NTS, they were reduced by IMO. In a parallel experiment, BP was monitored during restraint stress. The elevation of BP in response to single or repeated restraint stress was sustained during 2 h in controls and reduced after 70 min stress in EB treated rats. One month after withdrawal of EB treatment, the BP response to restraint was similar to that of rats which never received EB. The results demonstrate that estrogen can modulate responses to stress affecting HPA axis, CA biosynthesis, in central and peripheral noradrenergic systems, and BP.
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PMID:Estrogen modifies stress response of catecholamine biosynthetic enzyme genes and cardiovascular system in ovariectomized female rats. 1580 80

Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic system. Brain delivery of glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore the dopaminergic pathway in various animal models of PD. However, GDNF overexpression in the dopaminergic pathway leads to a time-dependent down-regulation of tyrosine hydroxylase (TH), a key enzyme in dopamine synthesis. In order to elucidate GDNF-mediated biochemical effects on dopaminergic neurons, we overexpressed GDNF in the intact rat striatum using a lentiviral vector-mediated gene transfer technique. Long-term GDNF overexpression led to increased GTP cyclohydrolase I (GTPCH I) activity and tetrahydrobiopterin (BH4) levels. Further, we observed a down-regulation of TH enzyme activity in morphologically intact striatal dopaminergic nerve terminals, as well as a significant decrease of dopamine levels in striatal tissue samples. These results indicate that long-term GDNF delivery is a major factor affecting dopamine biosynthesis via a direct or indirect modulation of TH and GTPCH I and further underscore the importance of assessing both GDNF dose and delivery duration prior to clinical application in order to circumvent potentially adverse pharmacological effects on the biosynthesis of dopamine.
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PMID:Long-term glial cell line-derived neurotrophic factor overexpression in the intact nigrostriatal system in rats leads to a decrease of dopamine and increase of tetrahydrobiopterin production. 1593 64

One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6-pyruvoyltetrahydropterin synthase (PTS) gene-disrupted (Pts(-/-)) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts(-/-) mice by transgenic introduction of human PTS cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency. The DPS-rescued (Pts(-/-), DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency. Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.
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PMID:Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities. 1613 92

Oxidative stress is believed to contribute to the pathophysiology of Parkinson's disease, in which nigrostriatal dopaminergic (DA) neurons undergo degeneration. Identification of endogenous molecules that contribute to generation of oxidative stress and vulnerability of these cells is critical in understanding the etiology of this disease. Exposure to tetrahydrobiopterin (BH4), the obligatory cofactor for DA synthesis, was observed previously to cause oxidative damage in DA cells. To demonstrate the physiological relevance of this observation, we investigated whether an overproduction of BH4 and DA might actually occur in vivo, and, if it did, whether this might lead to oxidative damage to the nigrostriatal system. Immobilization stress (IMO) elevated BH4 and DA and their synthesizing enzymes, tyrosine hydroxylase and GTP cyclohydrolase I. This was accompanied by elevation of lipid peroxidation and protein-bound quinone, and activities of antioxidant enzymes. These increases in the indices of oxidative stress appeared to be due to increased BH4 synthesis because they were abolished following administration of the BH4 synthesis inhibitor, 2,4-diamino-6-hydroxy-pyrimidine. IMO also caused accumulation of neuromelanin and degeneration of the nigrostriatal system. These results demonstrate that a severe stress can increase BH4 and DA and cause oxidative damages to the DA neurons in vivo, suggesting relevance to Parkinson's disease.
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PMID:Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system. 1618 15

Neurotrophins are essential for the development and survival of the catecholaminergic neurons. GTP cyclohydrolase I (GCH) is the first and rate-limiting enzyme in the biosynthesis of 5,6,7,8-tertahydrobiopterin (BH4), the required cofactor for tyrosine hydroxylase. Previously, we reported that TH requires the Ras/mitogen-activated protein kinase kinase (MEK) pathway for its induction by nerve growth factor (NGF). Here, we examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment, and the increase was repressed by pretreatment with U0126, an MEK1/2 inhibitor, but not with protein kinase A (PKA), phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and c-Jun NH2-terminal kinase (JNK) inhibitors. Induction of GCH mRNA by NGF was also abolished by pretreatment with U0126. The human GCH promoter activity was significantly enhanced by NGF treatment. Deletion analysis showed that the 465-bp 5'-flanking region is responsible for NGF-enhanced promoter activity. These data suggest that the Ras-MEK pathway is required for coordinate expression of the GCH and TH genes induced by neurotrophins.
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PMID:Nerve growth factor-induced expression of the GTP cyclohydrolase I gene via Ras/MEK pathway in PC12D cells. 1619 Aug 74

The authors present four cases from two unrelated families with young-onset predominant cervical dystonia with a dramatic sustained response to levodopa. Onset age was 12 years (range 9 to 15). Additional symptoms included postural hand tremor and laryngeal dystonia. Genetic testing for GTP cyclohydrolase I, tyrosine hydroxylase, and sepiapterin reductase was negative. These cases may represent new forms of dopa-responsive dystonia. Levodopa is advisable in all patients with young-onset cervical dystonia.
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PMID:Familial dopa-responsive cervical dystonia. 1650 23

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. There are at least three causative genes for DRD: (1) the GCH1 gene on chromosome 14q22.1-q22.2, which encodes GTP cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway for tetrahydrobiopterin (BH4; the essential cofactor for tyrosine hydroxylase [THI]), (2) the TH gene on 11 p15.5, coding for the enzyme TH that catalyzes the rate-limiting step in the catecholamine biosynthesis, and (3) an as yet undefined gene on 14q13 (DYT14). In reports on DRD, in which conventional genomic DNA sequencing of GCH1 was conducted in a relatively large number of pedigrees, mutations in the coding region (including the splice sites) of this gene were found in approximately 60% (range: 49-79%) of DRD families. In our series, after conducting additional GCH1 testing (Southern blotting, cDNA sequencing, etc.) and TH analysis, 86% of families with DRD or dystonia with motor delay (an intermediate phenotype between GTPCH-deficient DRD [mild] and GTPCH-deficient hyperphenylalaninemia [severe]) had identifiable GCH1 or (rarely) TH mutations. Up to the present, only one pedigree with autosomal dominant DRD linked to the DYT14 locus has been reported. Neuropathological findings (no Lewy bodies and a normal population of cells with reduced melanin in the substantia nigra) in DRD patients with GTPCH dysfunction were similar to those in a patient with DYT14 dystonia. There have been no reports of autopsied patients with TH-deficient DRD. Neurochemical data suggest that striatal dopamine reduction in GTPCH-deficient DRD is caused not only by decreased TH activity resulting from a low cofactor (BH4) level but also by actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum, especially in the putamen, may be due to a diminished regulatory effect of BH4 on stability (rather than expression) of TH molecules or to a dysfunction of TH protein transport from the substantia nigra to the striatum. The extent of striatal TH protein loss may be critical in determining DRD symptomatology and could contribute to gender-related incomplete penetrance of GCH1 mutations in GTPCH-deficient DRD families. Notwithstanding the discovery of the three causative loci for DRD, a therapeutic trial with low doses of levodopa is still the most practical approach to the diagnosis of this treatable disorder. The trial should be considered in all children with dystonic and/or parkinsonian symptoms or with unexplained gait disorders. Analyses of total biopterin and neopterin as well as neurotransmitter metabolites in CSF appear to be useful for the diagnosis of GTPCH-deficient DRD (the major form of DRD) and of TH-deficient DRD (the mild form of TH deficiency). Findings of the precise mechanism of striatal TH protein loss in GTPCH-deficient DRD, the actual status of dopaminergic systems in TH-deficient DRD, and the novel causative gene on the DYT14 locus will better define the pathogenesis of DRD.
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PMID:[Dopa-responsive dystonia: clinical, genetic, and biochemical studies]. 1654 91

Autosomal recessive Parkinson's disease (PD) with early-onset may be caused by mutations in the parkin gene (PARK2). We have ascertained 87 Danish patients with an early-onset form of PD (age at onset < or =40 years, or < or =50 years if family history is positive) in a multicenter study in order to determine the frequency of PARK2 mutations. Analysis of the GTP cyclohydrolase I gene (GCH1) and the tyrosine hydroxylase gene (TH), mutated in dopa-responsive dystonia and juvenile PD, have also been included. Ten different PARK2 mutations were identified in 10 patients. Two of the patients (2.3%) were found to have homozygous or compound heterozygous mutations, and eight of the patients (9.2%) were found to be heterozygous. A mutation has been identified in 10.4% of the sporadic cases and in 15.0% of cases with a positive family history of PD. One patient was found to be heterozygous for both a PARK2 mutation and a missense mutation (A6T) in TH of unknown significance. It cannot be excluded that both mutations contribute to the phenotype. No other putative disease causing TH or GCH1 mutations were found. In conclusion, homozygous, or compound heterozygous PARK2 mutations, and mutations in GCH1 and TH, are rare even in a population of PD patients with early-onset of the disease.
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PMID:Low frequency of Parkin, Tyrosine Hydroxylase, and GTP Cyclohydrolase I gene mutations in a Danish population of early-onset Parkinson's Disease. 1664 17

The nuclear receptor Nurr1 is essential for the development of midbrain dopamine neurons and appears to be an important regulator of dopamine levels as adult Nurr1-null heterozygous (+/-) mice have reduced mesolimbic/mesocortical dopamine levels. The mechanism(s) through which reduced Nurr1 expression affects dopamine levels has not been determined. Quantitative real-time PCR revealed a significant reduction in tyrosine hydroxylase (TH) and GTP cyclohydrolase (GTPCH) mRNA in ventral midbrain of +/- mice as compared to wild-type mice (+/+). The effect on TH expression was only observed at birth, while reduced GTP cyclohydrolase was also observed in the adult ventral tegemental area. No differences in dopamine transporter, vesicular monoamine transporter, dopamine D2 receptor or aromatic amino acid decarboxylase were observed. Since TH and GTPCH are both involved in dopamine synthesis, regulation of in vivo TH activity was measured in these mice. In vivo TH activity was reduced in nucleus accumbens and striatum of the +/- mice (24.7% and 15.7% reduction, respectively). In the striatum, gamma-butyrolactone exacerbated differences on +/- striatal TH activity (29.8% reduction) while haloperidol equalized TH activity between the +/+ and +/-. TH activity in the nucleus accumbens was significantly reduced in all conditions measured. Furthermore, dopamine levels in the striatum of +/- mice were significantly reduced after inhibition of dopamine synthesis or after haloperidol treatment but not under basal conditions while dopamine levels in the nucleus accumbens were reduced under basal conditions. Based on these data the +/- genotype results in changes in gene expression and impairs dopamine synthesis which can affect the maintenance of dopamine levels, although with differential effects between mesolimbic/mesocortical and nigrostriatal dopamine neurons. Together, these data suggest that Nurr1 may function to modify TH and GTPCH expression and dopamine synthesis.
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PMID:Reduced tyrosine hydroxylase and GTP cyclohydrolase mRNA expression, tyrosine hydroxylase activity, and associated neurochemical alterations in Nurr1-null heterozygous mice. 1678 8


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