Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have used recombinant retroviruses encoding the tyrosine hydroxylase (TH) gene to transduce various cell lines, including fibroblasts (NIH-3T3), a pituitary tumor cell line (AtT20), and a pancreatic endocrine line (RIN). These genetically modified cells, synthesizing either 3,4-dihydroxyphenylalanine, dopamine, or both, are potential donors for treatment of Parkinson's disease. However, the levels of TH protein in such transduced cells have been low and heterogeneous. Using several modified versions of retrovirus vectors encoding TH, we demonstrated that protein stability is an important factor governing levels of TH in NIH-3T3 fibroblasts. Whereas low levels of TH protein were observed in infected NIH-3T3 cells, high levels of a TH-beta gal fusion protein were found. This difference was due to a significantly longer half-life of the TH-beta gal fusion protein relative to TH alone. However, the TH-beta gal fusion protein was found to be enzymatically inactive. We also found that the half-life of the endogenous TH protein in PC-12 cells is sevenfold longer than the TH protein in transduced fibroblasts, implying that a cell-type specific regulator or mechanism may stabilize TH in catecholaminergic cells.
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PMID:The stability of endogenous tyrosine hydroxylase protein in PC-12 cells differs from that expressed in mouse fibroblasts by gene transfer. 750 76

We report the first neuropathological and neurochemical study of a patient with dopa-responsive dystonia. She had onset of foot dystonia at age 5 years and by age 8 years it was generalized with prominent right leg and arm involvement. On levodopa 750 mg daily she had complete symptomatic improvement that was sustained for 11 years until death. Pathological studies revealed normal numbers of hypopigmented substantia nigra neurons, normal tyrosine hydroxylase (TH) immunoreactivity and TH protein in the SN, no inclusion bodies or gliosis, and no evidence of a degenerative process in the striatum. Biochemical studies revealed reduced dopamine in the substantia nigra and striatum (8% in the putamen and 18% of control in the caudate) with a similar but not identical subregional distribution as in idiopathic Parkinson's disease. In the striatum, TH protein and TH activity was reduced, with the loss more pronounced in the putamen than the caudate. The GBR 12935 binding to DA transporter was normal in the caudate and at the lower end of the range of control values in the putamen. We conclude that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the major disturbance in dopa-responsive dystonia.
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PMID:Dopa-responsive dystonia: pathological and biochemical observations in a case. 815 63

Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitrary subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.
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PMID:Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon. 791 4

To analyze the roles of transcriptional and post-transcriptional regulatory mechanisms of tyrosine hydroxylase (TH) gene expression during dopaminergic denervation in Parkinson's disease (PD), the cellular content of TH messenger RNA (mRNA) and TH protein in the substantia nigra were compared in control subjects and patients with PD. The average amounts of TH mRNA as well as those of TH protein per neuron were variable among controls but correlated to each other. In PD patients, both TH mRNA and TH protein content in nigral neurons were reduced relative to controls, however, the ratio between TH protein and TH mRNA levels was unaffected. The data suggest that, in PD: (1) TH protein content is decreased in the surviving nigral dopaminergic neurons, most likely as a result of a lowered TH mRNA cellular content. Thus the surviving neurons at end stages of the disease may be in a premorbid state. (2) The TH mRNA translation rate is not modified to compensate for dopamine deficiency.
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PMID:Tyrosine hydroxylase protein and messenger RNA in the dopaminergic nigral neurons of patients with Parkinson's disease. 809 54

Parkinson's disease is characterized by massive degeneration of the melanized dopaminergic neurons in the substantia nigra. The functional capacity of the surviving nigral neurons is affected, as indicated by the subnormal levels of tyrosine hydroxylase (TH) mRNA in these neurons and the presence in the parkinsonian mesencephalon of melanized neurons lacking TH immunoreactivity. This is apparently in contraction with the known overactivity of dopamine synthesis and release that occurs in the remaining dopaminergic terminals. To test the ability of the surviving neurons to express TH protein, a semiquantitative immunocytochemical method was developed. The relative amounts of TH were estimated with a computer-assisted image analysis system in the dopaminergic neurons of representative mesencephalic sections of control and parkinsonian brains and for comparison in brains from patients with Alzheimer's disease. In control brains, the mean TH content per neuron differed from one subject to another and between the different dopaminergic cell groups of the mesencephalon in the same subject. Within a given dopaminergic region, the level of TH was variable among neurons. In patients with Parkinson's disease, the ratio of TH protein content per neuron in the substantia nigra by reference to that of the central gray substance was reduced. In patients with Alzheimer's disease, the amount of TH was selectively reduced in the remaining dopaminergic neurons of the ventral tegmental area, a region characterized by a loss in dopaminergic neurons. The decrease in cellular TH content might therefore be related to the presence of the neurodegenerative process in the area considered. In patients with Parkinson's disease, the incapacity of the surviving neurons to express normal TH levels may reduce the efficiency of the hyperactivity mechanisms that develop in the remaining striatal dopaminergic terminals.
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PMID:Immunocytochemical quantification of tyrosine hydroxylase at a cellular level in the mesencephalon of control subjects and patients with Parkinson's and Alzheimer's disease. 810 78

TH is a tetrahydrobiopterin-requiring, iron-containing monooxygenase. It catalyses the conversion of L-tyrosine to L-dopa, which is the first, rate-limiting step in the biosynthesis of catecholamines (dopamine, noradrenaline and adrenaline), the central and sympathetic neurotransmitters and adrenomedullary hormones. The cofactor of TH is tetrahydrobiopterin, which is synthesized from GTP in three steps. The TH gene consists of 14 exons only in humans and 13 exons in animals. Human TH exists in four isoforms (hTH1-4) that are produced by alternative mRNA splicing from a single gene. A single mRNA and protein corresponding to hTH1 exists in non-primates. Monkey TH exists in two isoforms, corresponding to hTH1 and hTH2. TH activity is regulated in the short term by feedback inhibition of catecholamines in competition with tetrahydrobiopterin, and by activation and deactivation due to phosphorylation and dephosphorylation, mainly at Ser-19 and Ser-40 of hTH1. The multiple TH isoforms in humans and monkeys have additional phosphorylation, resulting in more subtle regulation. In long-term regulation under stress conditions, TH protein is induced. CRE and AP1 in the 5' flanking region of the TH gene may be the main functional elements for TH gene expression. TH may be closely related to the pathogenesis of neurological diseases, such as dystonia and Parkinson's disease, psychiatric diseases, such as affective disorders and schizophrenia, as well as cardiovascular diseases. The TH gene may prove useful in gene therapy to compensate for decreased levels of catecholamines in neurological diseases, for example, for supplementation of dopamine in Parkinson's disease.
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PMID:Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. 882 46

The molecular characteristics of midbrain dopamine (DA) neurons have been extensively studied in Parkinson's disease (PD). No such studies of the characteristics of midbrain DA neurons in Alzheimer's disease (AD) or Alzheimer's disease with parkinsonism (AD/Park) have been published. We examined the levels of tyrosine hydroxylase (TH) protein, and the expression of TH and dopamine transporter (DAT) mRNAs, in midbrain neurons of PD, AD, and AD/Park cases. In PD, the loss of TH protein in the ventral tier of the substantia nigra pars compacta (SNpc) of the PD group in accompanied by severe losses in the number of neurons that express TH mRNA and DAT mRNA (74% loss). Remaining neurons show a shift to higher concentrations of TH mRNA but a shift to lower concentrations of DAT mRNA per cell. Hence, there is evidence that compensation in the remaining neurons can elevate concentrations of TH mRNA and lower DAT mRNA. Alternatively, there may be a predilection for a loss of neurons with high levels of DAT mRNA and low TH mRNA levels within the SNpc of PD cases. There was no change in TH protein but an elevation of TH mRNA concentrations per neuron without any change in concentrations of DAT mRNA in the AD group. The AD/Park group did not exhibit changes in the level of TH protein, but showed a small loss (26%) of neurons in the SNpc and a greater loss in other regions of the midbrain (43-53%). Remaining DA neurons showed a marked shift to lower concentrations of DAT mRNA per neuron and a nonsignificant shift in cellular concentration of TH mRNA to higher levels. This is consistent with our previous work showing that with AD/Park there is a significant reduction in the number of DAT sites located on DA terminals in the striatum, but the midbrain neurons have not died. Our results indicate that the differential regulation of mRNAs encoding TH and DAT is similar in the parkinsonian disorders (PD and AD/Park) even though the degree of cell death is very different. This might suggest that compensatory events occur in these DA neurons in AD/Park that are similar to those in PD and that result in differential effects on mRNAs encoding TH and DAT proteins.
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PMID:Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs in midbrain of subjects with Parkinson's, Alzheimer's with parkinsonism, and Alzheimer's disease. 939 11

Tyrosine hydroxylase (TH) gene is the rate-limiting enzyme in the synthesis of catecholamines. Functional polymorphisms of the TH gene may be involved in the pathogenesis of neuropsychiatric diseases such as schizophrenia, affective disorders, and Parkinsonism. This study examined a possible association of two polymorphisms, both of which result in an amino acid change of the TH protein, with schizophrenia and Parkinson's disease (PD). The Val81Met polymorphism is a common variation, although its effect on the enzyme expression is unclear. Leu205Pro polymorphism is a rare mutation that is reported to cause Parkinsonism in infancy for individuals who are homozygous for the mutated type. We genotyped a Japanese sample of 194 schizophrenics, 99 patients with PD, and 161 controls for the Val81Met polymorphism by using mis-match PCR and digestion by the restriction enzyme BalI. There was no significant allelic or genotypic association of the Val81Met polymorphism with schizophrenia or PD. The Leu205Pro polymorphism was examined by using PCR and digestion by AluI; however, there was no individual who carried the mutated type of Pro205 among 50 schizophrenics or 50 patients with PD. Thus we obtained no evidence for the involvement of the two structural mutations of the TH gene in the pathogenesis of schizophrenia or PD.
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PMID:Association study of structural mutations of the tyrosine hydroxylase gene with schizophrenia and Parkinson's disease. 961 51

The decrement in dopamine levels exceeds the loss of dopaminergic neurons in Parkinson's disease (PD) patients and experimental models of PD. This discrepancy is poorly understood and may represent an important event in the pathogenesis of PD. Herein, we report that the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is a selective target for nitration following exposure of PC12 cells to either peroxynitrite or 1-methyl-4-phenylpyridiniun ion (MPP+). Nitration of TH also occurs in mouse striatum after MPTP administration. Nitration of tyrosine residues in TH results in loss of enzymatic activity. In the mouse striatum, tyrosine nitration-mediated loss in TH activity parallels the decline in dopamine levels whereas the levels of TH protein remain unchanged for the first 6 hr post MPTP injection. Striatal TH was not nitrated in mice overexpressing copper/zinc superoxide dismutase after MPTP administration, supporting a critical role for superoxide in TH tyrosine nitration. These results indicate that tyrosine nitration-induced TH inactivation and consequently dopamine synthesis failure, represents an early and thus far unidentified biochemical event in MPTP neurotoxic process. The resemblance of the MPTP model with PD suggests that a similar phenomenon may occur in PD, influencing the severity of parkisonian symptoms.
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PMID:Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 963 6

The mesolimbic dopamine (DA) system preferentially innervates the D3 receptor, whereas the D2 receptor is, in addition, a target of the nigrostriatal DA system. In human brain D3 receptors and D3 mRNA-expressing neurons are largely segregated to brain regions that are the targets of the mesolimbic DA system and the efferents of the "limbic striatum." Thus, D3 receptors may regulate effects of DA on the "limbic" cortico-striatal-pallidal-thalamic-cortical loop. The nigrostriatal DA system is considerably more damaged in Parkinson's disease (PD) than the mesolimbic DA system. We report here, using radioligands selective for the D2 and D3 receptor, that these receptors are independently changed in PD. Tissue collected at autopsy from nine subjects with a diagnosis of PD and eight age-matched subjects with no evidence of a neurologic disorder was processed for [125I]epidepride binding to D2 receptors, [125I] trans-7-OH-PIPAT binding to D3 receptors, [125I]RTI-55 for the DA transporter (DAT), and immunoautoradiography for tyrosine hydroxylase (TH) using autoradiographic methods. Dopaminergic innervation to the caudal putamen was profoundly reduced and to a lesser extent in the rostral putamen in PD. DAT sites but not TH protein levels were reduced in the nucleus accumbens (NAS) in PD compared with age-matched control subjects. This is consistent with a loss of dopaminergic innervation from the mesolimbic DA system but elevation in TH production. D3 receptors were significantly reduced in PD by 40-45% particularly in the NAS and putamen. D2 receptors were elevated in PD in the dorsal putamen by 15%. The reduction in D3 receptor number was not observed in PD cases with a diagnosis of less than 10 years. The changes in DA D3 receptor number is interesting in light of the development of antiparkinsonian agents that are D3-preferring agonists.
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PMID:Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson's disease. 975 47


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