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

Fibroblasts (NRK-49F) were transfected with human type 2 tyrosine hydroxylase (TH; EC 1.14.16.29) cDNA, to clarify the mechanism involved in amelioration of parkinsonism by intracerebral grafting of catecholaminergic neurons and to investigate its possible use as a donor material. These genetically manipulated fibroblasts did not develop into a mass of tissue, and survived well in the host striatum. Expression of the TH minigene in the cells was successful even when they were transplanted into the host brain. Intracerebral microdialysis revealed that a measurable amount of L-3,4-dihydroxyphenylalanine (L-DOPA) was not spontaneously released from the implanted cells into the host striatum. However, release of a large amount of L-DOPA from the cells was observed when (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) was perfused through a dialysis probe. Finally, we investigated whether these BH4-dependent L-DOPA-secreting fibroblasts are able to ameliorate the abnormal behavior of 6-hydroxydopamine-treated rats. Apomorphine-induced rotating behavior was not reversed by the grafting alone, whereas a marked reduction in drug-induced circling was observed temporarily after BH4 was perfused around the implanted cells. These findings indicate that TH cDNA-transfected non-neuronal cells might be able to be used as donor material for intracerebral grafting and ameliorate the abnormal behavior of rats with experimental Parkinson's disease.
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PMID:Tetrahydrobiopterin-dependent functional recovery in 6-hydroxydopamine-treated rats by intracerebral grafting of fibroblasts transfected with tyrosine hydroxylase cDNA. 135 49

Two patients with Parkinson's disease were treated with 1 g tetrahydrobiopterin (BH4) for 5 days. Clinical improvement was not observed. In the cerebrospinal fluid (CSF) a 4-8 fold increase in the concentration of homovanillic acid (HVA), and a 3-fold increase in the concentration of 5-hydroxyindole acetic acid (5-HIAA) was measured. However, the concentration of HVA reached, was only approximately half as high, as that of patients treated with madopar (DOPA + benserazid). In urine, the excretion of HVA increased 13-37 fold, when the patients were treated with madopar, whereas no increase in the HVA excretion was measured after the BH4 administration. Additionally, 2 patients with Parkinson's disease were treated with 1 g BH4 in combination with 15 g tyrosine for 3 days, and 1 parkinsonian patient was treated with 15 g tyrosine daily for 7 weeks. No increase in the CSF concentrations of HVA or 5-HIAA was observed. The results suggest, the BH4 in the dosage used, is not effective in the treatment of Parkinson's disease.
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PMID:Tetrahydrobiopterin and Parkinson's disease. 247 6

Marked fluctuations in mobility, known as the on-off phenomenon, frequently emerge during the course of chronic treatment with levodopa in patients with Parkinson's disease. Similar fluctuations in mobility and mental status have been observed in a 10-year-old Japanese girl with tetrahydrobiopterin deficiency (BH4 deficiency) while receiving neurotransmitter and biopterin supplement. In order to define the underlying mechanisms for the phenomenon in our patient, we studied the temporal relationship between plasma levodopa levels and clinical status during oral (2.0 mg/kg per day) and continuous intravenous (2.0 mg/kg per 12 h) administration of the drug. Following each oral levodopa dose, the plasma concentration of levodopa peaked at 60-90 ng/ml within 60 min and fell to 5-15 ng/ml within 2 h. The clinical state of the patient varied acutely in parallel with the plasma levodopa concentrations. The clinical swings completely disappeared when the plasma levodopa concentrations were stabilized between 120-150 ng/ml by continuous infusion. Paradoxically, on awakening from sleep, she was invariably ambulatory despite very low plasma levodopa levels (less than 10 ng/ml). These observations indicate that the on-off phenomenon in our patient reflect the fluctuations of plasma levodopa levels as demonstrated in Parkinson's disease, but there may be substantial differences in levodopa transport across the blood-brain barrier and/or striatal dopamine-receptor interaction between Parkinson's disease and BH4 deficiency.
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PMID:On-off phenomenon in a child with tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency (BH4 deficiency). 264 29

Although intracerebral grafting has become a new strategy for the treatment of Parkinson's disease, many problems related to the grafts remain. We focused on primary skin fibroblasts as grafts. Rat primary skin fibroblasts were transfected with a retrovirus vector containing the cDNA of human tyrosine hydroxylase (TH) (pLTHSNL) or cytomegalovirus promoter (pCTHSNL) as a foreign promoter, and catecholamine production and release by these genetically modified fibroblasts, were analyzed in vitro immunocytochemically and by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The cells were supplemented with biopterin (BH4; (6R)-L-erythro-tetrahydrobiopterin), a cofactor required for TH activity, and they produced and released L-DOPA into the culture medium. When exposed to the combination of a foreign promoter and BH4, L-DOPA production increased in a time-dependent manner, and was unaffected by the number of cell-passages or the duration of liquid-nitrogen freezing. This suggests that the foreign gene (THcDNA)-containing retrovirus vector had integrated into the chromosomal DNA of the target cells (fibroblasts). Primary fibroblasts can be easily obtained and cultured. Thus, genetically modified primary skin fibroblasts transfected with THcDNA using this retrovirus vector system appear to be a promising graft for transplantation and gene therapy of Parkinson's disease in the future.
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PMID:[L-DOPA-producing primary fibroblasts genetically modified with a retrovirus vector system]. 754 38

Nitric oxide (NO) is a recently discovered endogenous mediator of vasodilatation, neurotransmission, and macrophage cytotoxicity. NO is thought to have a function in memory and in long-term potentiation. At high concentrations NO is neurotoxic and may play a role in neurodegeneration. NO is formed from L-arginine by the enzyme NO synthase (NOS), for which tetrahydrobiopterin (BH4) is a necessary co-factor. Alzheimer's disease (AD) and, to a lesser degree, Parkinson's disease (PD) are thought to be associated with increased microglial activity, suggesting that NO production may be increased. Alternatively, in circumstances of reduced levels of intracellular L-arginine or BH4, NO production is diminished and neurotoxic oxygen radicals may be produced. Since BH4 is decreased in AD and PD brains, these diseases may be associated with decreased NO production. We investigated these two alternatives by measuring the NO degradation products nitrite and nitrate in cerebrospinal fluid (CSF) of PD (n = 103), AD (n = 13), and multiple system atrophy (MSA; n = 14) patients and controls (n = 20). We found for all patient groups, compared with controls, significantly decreased levels of nitrate, but not nitrite. This finding seems to indicate a decreased NO production of the central nervous system (CNS) in these neurodegenerative disorders.
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PMID:Decreased cerebrospinal fluid nitrate levels in Parkinson's disease, Alzheimer's disease and multiple system atrophy patients. 813 11

The use of primary human fetal tissue in the treatment of neurodegenerative disorders, while promising, faces several difficult technical and ethical issues. An alternative approach that would obviate these problems would be to use immortalized cell lines of human fetal central nervous system origin. An immortalized human fetal astrocyte cell line (SVG) has been established (45) and herein we describe the in vitro and in vivo characteristics of this cell line which suggest that it may be a useful vehicle for neural transplantation. The SVG cell line is vimentin, GFAP, Thy 1.1 and MHC class I positive, and negative for neurofilament and neuron specific enolase, consistent with its glial origin. To determine whether the cell line could be used as a drug delivery system, a cDNA expression vector for tyrosine hydroxylase was constructed (phTH/Neo) and stably expressed in the SVG cells for over 18 months as demonstrated by immunohistochemistry and Western blotting of the stable transfectants. HPLC analysis of the supernatant from these cells, termed SVG-TH, consistently found 4-6 pmol/ml/min of l-dopa produced with the addition of BH4 to the media. Furthermore, in cocultivation experiments with hNT neurons, PC-12 cells and primary rat fetal mesencephalic tissue, both the SVG and SVG-TH cells demonstrated neurotrophic potential, suggesting that they constituitively express factors with neuroregenerative potential. To determine the viability of these cells in vivo, SVG-TH cells were grafted into the striatum of Sprague-Dawley rats and followed over time. A panel of antibodies was used to unequivocally differentiate the engrafted cells from the host parenchyma, including antibodies to: SV40 large T antigen (expressed in the SVG-TH cells), human and rat MHC class 1, vimentin, GFAP, and tyrosine hydroxylase. While the graft was easily identified with the first week, over the course of a four week period of time the engrafted cells decreased in number. Concomittantly, rat CD4 and CD8 expression in the vicinity of the graft increased, consistent with xenograft rejection. When the SVG-TH cells were grafted to the lesioned striatum of a 6-hydroxydopamine lesioned rats, rotational behavior of the rat decreased as much as 80% initially, then slowly returned to baseline over the next four weeks, parallelling graft rejection. Thus, the SVG-TH cells can induce a functional recovery in an animal model of Parkinson's disease, however as a xenograft, the SVG cells are recognized by the immune system.
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PMID:Expression of tyrosine hydroxylase in an immortalized human fetal astrocyte cell line; in vitro characterization and engraftment into the rodent striatum. 868 28

Gene transfer of tyrosine hydroxylase (TH) in animal models of Parkinson's disease (PD), using either genetically modified cells or recombinant virus vectors, has produced partial restoration of behavioral and biochemical deficits. The limited success of this approach may be related to the availability of the cofactor, tetrahydrobiopterin (BH4), because neither the dopamine-depleted striatum nor the cells used for gene transfer possess a sufficient amount of BH4 to support TH activity. To determine the role of BH4 in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase l; an enzyme critical for BH4 synthesis. In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH4 and 3, 4-dihydroxy-L-phenylalanine. To examine further the importance of GTP cyclohydrolase I in gene therapy for PD, in vivo micro-dialysis was used to assess the biochemical changes in the dopamine-denervated striatum containing grafts of genetically modified fibroblasts. Only denervated striata grafted with fibro-blasts possessing both TH and GTP cyclohydrolase I genes displayed biochemical restoration. However, no significant differences from controls were observed in apomorphine-induced rotation. This is partly attributable to a limited duration of gene expression in vivo. These differences between fibroblasts transduced with TH alone and those additionally modified with the GTP cyclohydrolase I gene indicate that BH4 is critical for biochemical restoration in a rat model of PD and that GTP cyclohydrolase I is sufficient for production of BH4.
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PMID:Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts. 869 55

Although intracerebral grafting has become established as a new strategy for the treatment of Parkinson's disease, there are many problems regarding such grafts. We focused on the grafting of primary skin fibroblasts. Rat primary skin fibroblasts were transfected with a retrovirus vector containing cDNA of human tyrosine hydroxylase (TH) type 1 (LTHSNL) or of cytomegalovirus promoter (CTHSNL) as a foreign promoter. In these genetically modified fibroblasts, L-DOPA production and release were analyzed in vitro by immunocytochemistry and high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Being supplemented with the biopterin (BH4:(6R)-L-erythro-tetrahydrobiopterin) cofactors required for TH activity, these cells produced and released L-DOPA into the culture medium. When CTHSNL and BH4 were combined, L-DOPA production increased with time, regardless of the number of cell passages, or the duration of liquid nitrogen freezing. This suggests that the foreign gene (THcDNA) containing retrovirus vector integrates into the chromosomal DNA of the target cells (fibroblasts). Primary fibroblasts can be easily obtained and cultured. Thus, genetically modified primary skin fibroblasts transfected with a retrovirus vector system containing the TH cDNA may be promising grafts for transplantation and gene therapy in Parkinson's disease.
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PMID:Regulation of L-DOPA production by genetically modified primary fibroblasts transfected with retrovirus vector system. 888 19

Hereditary progressive dystonia with marked diurnal fluctuation (HPD, Segawa's disease), also known as DOPA-responsive dystonia (DRD), was found to be caused by mutation of GTP cyclohydrolase I (GCH) gene. GCH activity in mononuclear blood cells was decreased to less than 20% of the normal values. The decrease in GCH activity causes the decrease in tetrahydrobiopterin (BH4) levels, resulting in decreased tyrosine hydroxylase (TH) activity and finally in decreased dopamine levels in the nigrostriatal dopamine neurons. In contrast, GCH activity in mononuclear blood cells in juvenile parkinsonism was normal. Recessive dystonia was shown to have a point mutation in TH gene. Thus, HPD (Segawa's disease) is distinct from recessive dystonia and juvenile parkinsonism. Patients with Parkinson's disease had decreased GCH activity in parallel with the decreases in TH activity and dopamine in the striatum, probably as the results of cell death.
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PMID:[Molecular genetics of hereditary progressive dystonia (HPD/Segawa's disease)]. 896 84

From its characteristic clinical features, decrease of tyrosine hydroxylase (TH) in the terminal of the nigrostriatal (NS) dopamine (DA) neuron is considered the main lesion of HPD and the decrease of neopterin as well as biopterin in the cerebrospinal fluid suggested GTP cyclohydrolase I (GCH-I) as the responsible enzyme. By detecting the gene locus of GCH-I, Ichinose and his colleagues showed the abnormalities of GCH-I gene located on 14q 22.1 q22.2 as the cause of HPD. Since the first report of Ichinose et al, 11 mutations and frame shifts of the gene have been detected, in which the locus of abnormality differed among families but is identical in a family, but more than several families have been left with undetected abnormalities including those having linkage to 14q. However, the DNA of these families as well as those with detected gene abnormalities failed to synthesize GCH-I if inoculated with E. coli and the levels of GCH-I in mononuclear blood cells were below 20% of normal values in HPD patients while they were 37 and 38% in two asymptomatic carriers. Ratio of mutant mRNA of GCH-I gene was 28% in a patient and 8.3% in an asymptomatic case. These lines of evidence on GCH-I show HPD is a dominant inherited disorder with abnormalities of GCH-I gene. GCH-I is the limiting enzyme for synthesizing tetrahydrobiopterin (BH4), coenzyme transmitters for the synthesizing hydroxylases of aminergic neurotransmitters, but the affinity is the least for TH. This might cause a rather selective involvement of TH preserving serotonin synthesis un- or less affected. Fluoro-DOPA and [11C] racropride PET studies were normal in HPD. Studies of an autopsied case with dopa responsive dystonia, which was confirmed to have GCH-I gene abnormalities, neuropathologically revealed no abnormalities except for a decrease in melanin pigmentation in the substantia nigra and histochemically a decrease in TH enzyme activities and its protein only in the striatum. There was mild decrease of DA content, the interregional caudate/putamen and subregional rostrocaudal patterns which were similar to Parkinson disease, but subdivisionally different with predominant reduction in the ventral subdivision of the caudate nucleus. In the ventral part of the basal ganglia the striatal direct projection exists predominantly. Cases with recessive abnormalities of pteridin metabolism other than HPD, 6-pyruvoyl-tetra-hydropterin synthase (PSPS) deficiency and dihydropteridine reductase deficiency also show dystonia with diurnal fluctuation responding to levodopa, though not as marked as HPD. MPTP monkey studies revealed no involvement of striatal indirect pathway for peak dose dystonia. So it is suggested that in HPD, decrease of TH at the terminal of the NS-DA neuron due to partial reduction of GCH-I develops postural dystonia through the striatal direct projection in childhood with diurnal fluctuation depending on age and circadian variation of TH activities at the terminals.
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PMID:[Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation-HPD) and abnormalities in pteridin metabolism]. 912 93


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