Disease relevance of TH

• At stage III, nearly all ganglion cells are positive for TH [1].
• E, NE, chromogranin, TH, DBH, and PNMT were found in the normal human adrenal medulla and in pheochromocytomas [2].
• Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas [3].
• A better understanding of human TH gene regulation may have important implications both for the development of novel therapeutic approaches and the study of the pathogenesis of a variety of neurological illnesses, including Parkinson's disease, bipolar disorder, and schizophrenia [4].
• RESULTS: TH was demonstrated in 9 (43%) of 21 carcinoids and in all (100%) of 20 pheochromocytomas, DBH in 8 (38%) carcinoids and in 15 (75%) pheochromocytomas, and PNMT in 7 (33%) carcinoids and in 13 (65%) pheochromocytomas [5].

Psychiatry related information on TH

• The presence of these additional populations of TH-positive neurons in the adult primate CNS has implications for functional catecholamine neurotransmission, its derangement in disease and drug abuse, and its rescue by gene therapeutic maneuvers in neurodegenerative diseases such as Parkinson's disease [6].
• The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase [7].
• The localization of TH to the highly polymorphic INS locus provides four new restriction fragment length polymorphisms which should help determine rapidly whether defects in TH are responsible for bipolar affective disorder in the Old Order Amish and other populations [8].
• (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder [9].
• Individual differences were observed among control subjects in number and distribution of TH-immunoreactive (IR) perikarya, indicating that antemortem factors may regulate TH expression [10].

High impact information on TH

• Phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute a small family of monooxygenases that utilize tetrahydropterins as substrates [11].
• Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase [12].
• Safe and stable TH gene transfer into the denervated striatum may have potential for the genetic therapy of Parkinson's disease [13].
• However, although rich in donor-derived tyrosine hydroxylase-expressing neurons, the grafts exhibited expanding cores of undifferentiated mitotic neuroepithelial cells, which can be tumorigenic [14].
• Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice [15].

Chemical compound and disease context of TH

• The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients [3].
• RESULTS: When corrected for differences in tissue fibrosis, the expression of both TH (AF 0.45 +/- 0.1%, SR 0.09 +/- 0.03%, P = 0.02) and tissue NE (AF 358 +/- 49 pg/mg, SR 225 +/- 39 pg/mg, P = 0.04) was greater in atrial tissue of the AF cohort [16].
• Human glioblastoma ADF cells express tyrosinase, L-tyrosine hydroxylase and melanosomes and are sensitive to L-tyrosine and phenylthiourea [17].
• We previously showed that a line of C6 rat glioma cells that expresses a GFAP-TH transgene, C6-THA, displays increased transgene activity when differentiated by forskolin treatment [18].
• Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppresses growth of estrogen-induced pituitary prolactinomas [19].

Biological context of TH

• The data indicate that ERK activity is responsible for phosphorylating TH at Ser31 in intact cells and suggest that TH-Ser31 phosphorylation may be regulated by multiple signaling pathways that converge at or prior to the activation of the ERKs [20].
• There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A [21].
• Double-label experiments in late-stage tadpoles and juvenile bullfrogs revealed that the intensely TH-positive neurons are negative for NPY [1].
• During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases [22].
• Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations [23].

Anatomical context of TH

• In TH-null mice, adrenocortical cells were characterized by an increase in liposomes and by tubular mitochondria with reduced internal membranes, suggesting a hypofunctional state of these steroid-producing cells [24].
• As early as one week postinjection, the histochemical examination of the rat substantia nigra showed a reduced staining of neurons expressing TH followed by a loss of TH(+) neurons at later time points [25].
• Moreover, in a homogeneous background of methylated CpGs, a single CpG in the first exon of the gene is constantly either unmethylated or methylated in, respectively, TH-expressing or non-expressing cell lines, tissues and single cells [26].
• Nerve fibers immunoreactive (IR) for TH or positively stained for CF were not observed in association with scleral spur cells [27].
• A significant degree of specificity for this human TH minimal promoter was observed only for human neuronal progenitor cells (hNPCs), but not for TH-positive differentiated mouse primary striatal and substantia nigra cells, indicating a significant difference in TH gene regulation between the human and mouse systems [4].

Associations of TH with chemical compounds

• Enzyme activity correlated positively with age in all brain areas for MAO (with both benzylamine and tryptamine substrates) but no consistent pattern of correlation was found for COMT and TH [28].
• Moreover, cotransduction with these two AAV vectors resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p < 0.01) [29].
• BACKGROUND: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme guanosine triphosphate-cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydroxylase [TH]) is unknown [30].
• In order to identify new regulatory elements in this region acting on gene expression, the methylation profile of the TH CpG island was investigated using the bisulfite sequencing method [26].
• The overall methylation level of this region is correlated to TH-expressing and non-expressing status in cell lines and DNA demethylation treatment with 5-azacytidine increased TH expression [26].

Physical interactions of TH

• Sections dual immunoreacted for BNNF and tyrosine hydroxylase revealed a subpopulation of dopaminergic neurons (approximately 28%) within the pars compacta which contained retrogradely transported BDNF [31].
• Amounts of tyrosine hydroxylase immunoreactivity and radioligand binding to the norepinephrine transporter, monoamine oxidase A, and alpha2-adrenoceptors were measured [32].
• The TH subset cells interacted via short range cytokine-like factors, each cell type producing an autocrine factor and another factor which suppressed the development and proliferation of the other TH cell type [33].
• Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic paroxysmal dystonia [34].

Regulatory relationships of TH

• Only in anurans, the ventral aspect of the suprachiasmatic nucleus possesses a small population of AMi cells that express also TH immunoreactivity and most likely also express NPY [35].
• By comparing several human neurogenic cell lines, we found that GDNF-induced TH expression was only observed in the cells possessing Ret protein and coincided with the expression levels [36].
• TGF-beta1 increases tyrosine hydroxylase expression by a mechanism blocked by BMP-2 in human neuroblastoma SH-SY5Y cells [37].
• The cells of the supraoptic nucleus and PVN produce AVP or oxytocin and coexpress tyrosine hydroxylase [38].
• These results indicate that modulation of tyrosine hydroxylase gene expression may constitute one of the mechanisms involved in the control of dopamine transmission by neurotensin [39].

Other interactions of TH

• In contrast to the tyrosine hydroxylase tetramer structure, a very pronounced asymmetry is observed in the phenylalanine hydroxylase, caused by the occurrence of two alternate conformations in the hinge region that leads to the coiled-coil helix [40].
• Nonlinkage of bipolar illness to tyrosine hydroxylase, tyrosinase, and D2 and D4 dopamine receptor genes on chromosome 11 [41].
• Immunostaining showed that TH and AADC were coexpressed efficiently in the same striatal cells in vitro and in vivo [29].
• No TH, NPY, or VIP-positive ciliary muscle neurons were observed [42].
• The age-related increases in nigral alpha-synuclein were non-aggregated and strongly associated with age-related decreases in tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine production [43].

Analytical, diagnostic and therapeutic context of TH

• There was a 5-fold increase in the expression of proenkephalin mRNA (502.8 +/- 142% vs. 100 +/- 17.5%, P = 0.016) and a 2-fold increase in the expression of neuropeptide Y (213.4 +/- 41.2% vs. 100 +/- 59.9%, P = 0.014) in the TH-null animals as determined by quantitative TaqMan (Perkin-Elmer) PCR [24].
• These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD [44].
• The quantity of GH released (as assessed by both RIA and reverse hemolytic plaque assay) under basal and stimulated conditions did not differ among TH-hGH and WT pituitary cell cultures [45].
• In vitro complementary information was obtained: TH-positive cells represented about 3% of the total cell population after a week in culture, based upon accurate anatomical dissection [46].
• Double-staining immunohistochemistry showed that TH and SPR were colocalized in the SN dopamine neurons [47].

References