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)

Catecholamine biosynthesis is regulated by tyrosine hydroxylase (TH) requiring tetrahydrobiopterin (BH4) as the cofactor. We found four (human TH type 1-4) and two isoforms (TH type 1 and 2) in humans and monkeys, while non-primate animals have a single TH corresponding to human TH type 1. BH4 is synthesized from GTP, and GTP cyclohydrolase I (GCH) is the first and regulatory enzyme. Mutations in GCH gene were found to cause both GCH deficiency with autosomal recessive trait and hereditary progressive dystonia with marked diurnal fluctuation (HPD) (Segawa's disease)/or DOPA-responsive dystonia (DRD) with autosomal dominant trait. When GCH activity is decreased to less than 20% of the normal value, the activity of TH in the nigrostriatal dopaminergic neurons may be first decreased resulting in decreases in TH activity and dopamine level, and in the symptoms of HPD/DRD. In contrast to HPD/DRD, juvenile parkinsonism (JP) have normal GCH activity. In Parkinson's disease (PD), GCH, TH, and dopamine in the striatum may decrease in parallel, as the secondary effects caused by cell death.
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PMID:GTP cyclohydrolase I gene, tetrahydrobiopterin, and tyrosine hydroxylase gene: their relations to dystonia and parkinsonism. 918 49

To achieve local, continuous L-DOPA delivery in the striatum by gene replacement as a model for a gene therapy for Parkinson's disease, the present studies used high titer purified recombinant adeno-associated virus (rAAV) containing cDNAs encoding human tyrosine hydroxylase (hTH) or human GTP-cyclohydrolase I [GTPCHI, the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis] or both to infect the 6-OHDA denervated rat striatum. Striatal TH and GTPCHI staining was observed 3 weeks after rAAV transduction, with little detectable perturbation of the tissue. Six months after intrastriatal rAAV transduction, TH staining was present but apparently reduced compared with the 3 week survival time. In a separate group of animals, striatal TH staining was demonstrated 1 year after rAAV transduction. Double staining studies using the neuronal marker NeuN indicated that >90% of rAAV-transduced cells expressing hTH were neurons. Microdialysis experiments indicated that only those lesioned animals that received the mixture of MD-TH and MD-GTPCHI vector displayed BH4 independent in vivo L-DOPA production (mean approximately 4-7 ng/ml). Rats that received the hTH rAAV vector alone produced measurable L-DOPA (mean approximately 1-4 ng/ml) only after receiving exogenous BH4. L-Aromatic amino acid decarboxylase blockade, but not 100 mM KCl-induced depolarization, enhanced L-DOPA overflow, and animals in the non-hTH groups (GTPCHI and alkaline phosphatase) yielded minimal L-DOPA. Although elevated L-DOPA was observed in animals that received mixed hTH and hGTPCHI rAAV vectors, there was no reduction of apomorphine-induced rotational behavior 3 weeks after intrastriatal vector injection. These data demonstrate that purified rAAV, a safe and nonpathogenic viral vector, mediates long-term striatal hTH transgene expression in neurons and can be used to successfully deliver L-DOPA to the striatum.
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PMID:Characterization of intrastriatal recombinant adeno-associated virus-mediated gene transfer of human tyrosine hydroxylase and human GTP-cyclohydrolase I in a rat model of Parkinson's disease. 959 4

To investigate the biochemical requirements for in vivo L-DOPA production by cells genetically modified ex vivo in a rat model of Parkinson's disease (PD), rat syngeneic 9L gliosarcoma and primary Fischer dermal fibroblasts (FDFs) were transduced with retroviral vectors encoding the human tyrosine hydroxylase 2 (hTH2) and human GTP cyclohydrolase I (hGTPCHI) cDNAs. As GTPCHI is a rate-limiting enzyme in the pathway for synthesis of the essential TH cofactor, tetrahydrobiopterin (BH4), only hTH2 and GTPCHI cotransduced cultured cells produced L-DOPA in the absence of added BH4. As striatal BH4 levels in 6-hydroxydopamine (6-OHDA)-lesioned rats are minimal, the effects of cotransduction with hTH2 and hGTPCHI on L-DOPA synthesis by striatal grafts of either 9L cells or FDFs in unilateral 6-OHDA-lesioned rats were tested. Microdialysis experiments showed that those subjects that received cells cotransduced with hTH2 and hGTPCHI produced significantly higher levels of L-DOPA than animals that received either hTH2 or untransduced cells. However, animals that received transduced FDF grafts showed a progressive loss of transgene expression until expression was undetectable 5 weeks after engraftment. In FDF-engrafted animals, no differential effect of hTH2 vs hTH2 + hGTPCHI transgene expression on apomorphine-induced rotation was observed. The differences in L-DOPA production found with cells transduced with hTH2 alone and those cotransduced with hTH2 and hGTPCHI show that BH4 is critical to the restoration of the capacity for L-DOPA production and that GTPCHI expression is an effective means of supplying BH4 in this rat model of PD.
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PMID:In vivo L-DOPA production by genetically modified primary rat fibroblast or 9L gliosarcoma cell grafts via coexpression of GTPcyclohydrolase I with tyrosine hydroxylase. 962 61

1. Catecholamine (dopamine, norepinephrine, and epinephrine) biosynthesis is regulated by tyrosine hydroxylase (TH). TH activity is regulated by the concentration of the cofactor tetrahydrobiopterin (BH4), whose level is regulated by GTP cyclohydrolase I (GCH) activity. Thus, GCH activity indirectly regulates TH activity and catecholamine levels. 2. TH activity in the nigrostriatal dopaminergic neurons is most sensitive to the decrease in BH4. 3. Mutations of GCH result in reductions in GCH activity, BH4, TH activity, and dopamine, causing either recessively inherited GCH deficiency or dominantly inherited hereditary progressive dystonia [HPD; Segawa's disease; also called dopa-responsive dystonia (DRD)]. 4. In juvenile parkinsonism and Parkinson's disease, which have dopamine deficiency in the basal ganglia as HPD/DRD, the GCH gene may be normal, and the molecular mechanism of the dopamine deficiency in the basal ganglia is different from that in HPD/DRD.
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PMID:Molecular biology of catecholamine-related enzymes in relation to Parkinson's disease. 1007 65

Bone marrow stromal cells can be used as an alternative source of cells for neural transplantation and repair. Here, the efficacy of genetically modified marrow stromal cells was examined in a rat model of Parkinson disease. Rat marrow stromal cells (rMSCs) and human marrow stromal cells (hMSCs) were genetically engineered by transduction with retroviruses encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase I, the enzyme necessary for production of the tetrahydrobiopterin cofactor for TH (BH4). Transduced cells synthesized 3,4-dihydroxyphenylalanine (L-DOPA) in vitro and maintained their multipotentiality after retroviral transduction. To examine the cells in vivo, transduced rMSCs were injected into the striatum of 6-hydroxydopamine-lesioned rats. L-DOPA and metabolites were detected by microdialysis in the denervated striatum of rats that received doubly transduced rMSCs. Also, there was a significant reduction in apomorphine-induced rotation when compared with controls. The cells engrafted and survived for at least 87 days. However, expression of the transgenes ceased at about 9 days, an observation consistent with reports from other laboratories in which similar retroviruses were used to express transgenes in the brain.
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PMID:Multipotential marrow stromal cells transduced to produce L-DOPA: engraftment in a rat model of Parkinson disease. 1054 18

Astrocytes secreting a large amount of 3,4-dihydroxyphenylalanine (dopa) were generated by adenoviral transduction of the human tyrosine hydroxylase (TH) gene. After characterizing in vitro, the effect of transplantation of these astrocytes to the striatum of hemiparkinsonian model rats was investigated. Subconfluent cortical astrocytes were infected by replication-defect adenovirus type 5 carrying the human TH-1 gene or the LacZ reporter gene under the promoter of the glial fibrillary acidic protein (AdexGFAP-HTH-1, AdexGFAP-NL-LacZ). Dopa secretion was not evident at 3 days after the transduction of the HTH-1 gene but it increased from 7 days up to at least 4 months. The secretion was substrate (tyrosine)-dependent, and was enhanced by loading tetrahydrobioputerin (BH4) concentration-dependently. One-third of the hemiparkinsonian model rats, that were transplanted the HTH-1 gene-transduced astrocytes or introduced the direct injection of the viral vector to the striatum, showed a reduction of methamphetamine-induced rotations for at least 6 weeks. Apomorphine-induced rotation was decreased to the 50% level of the control's, but the reduction was obtained equally by the transplantation of HTH-1 gene-transduced or LacZ reporter gene-transduced astrocytes, or by the introduction of HTH-1 or LacZ gene carrying adenovirus. Treatment with FK506 for 3 weeks improved the late-phase apomorphine-induced rotations following the introduction of the HTH-1 gene carrying adenovirus. Histological examination revealed that, in animals that showed a reduction of methamphetamine-rotation, the TH positive astrocytes-like cells were distributed widely in the host striatum for at least 4 weeks. The number of TH positive astrocytes-like cells and their immunoreactivity decreased after 6 weeks when OX-41 positive microglias/macrophages were infiltrated. Data indicate that the adenoviral transduction of the human TH gene to astrocytes and its introduction to the striatum is a promising approach for the treatment of Parkinson's disease. However, the further technical improvements are required to optimize the adenoviral gene delivery, such as the control of viral toxicity and the regulation of the immune response.
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PMID:Dopa-producing astrocytes generated by adenoviral transduction of human tyrosine hydroxylase gene: in vitro study and transplantation to hemiparkinsonian model rats. 1061 14

The causative genes of two types of hereditary dopa-responsive dystonia (DRD) due to dopamine (DA) deficiency in the nigrostriatum DA neurons have been elucidated. Autosomal dominant DRD (AD-DRD) was originally described by Segawa as hereditary progressive dystonia with marked diurnal fluctuation (HPD). We cloned the human GTP cyclohydrolase I (GCH1) gene, and mapped the gene to chromosome 14q22.1-q22.2 within the HPD/DRD locus, which had been identified by linkage analysis. GCH1 isthe rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase (TH), which is the first and rate-limiting enzyme of DA synthesis. We proved that the GCH1 gene is the causative gene for HPD/DRD based on the identification of mutations of the gene in the patients and decreases in the enzyme activity expressed in mononuclear blood cells to 2-20% of the normal value. About 60 different mutations (missense, nonsense, and frameshift mutations) in the coding region or in the exon-intron junctions of the GCH1 gene have been reported in patients with AD-DRD all over the world. Recent findings indicate that the decreased GCH1 activity in AD-DRD may be caused by the negative interaction of the mutated subunit with the wild-type one, i.e., a dominant negative effect, and/or by decreases in the levels of GCH1 mRNA and protein caused by inactivation of one allele of the GCH1 gene. Autosomal recessive DRD (AR-DRD) with Segawa's syndrome was discovered in Germany. The AR-DRD locus was mapped to chromosome 11p15.5 in the chromosomal site of the TH gene. In the AR-DRD with Segawa's syndrome, a point mutation in TH (Gln381Lys) resulted in a pronounced decrease in TH activity to about 15% of that of the wild type. Several missense mutations in the TH gene have been found in AR-DRD in Europe. The phenotype of AR-DRD with the Leu205Pro mutation in the TH gene, which produces a severe decrease in TH activity to 1.5% of that of the wild type, was severe, not dystonia/Segawa's syndrome, but early-onset parkinsonism. However, a marked improvement of all clinical symptoms with a low dose of L-dopa was reported in AR-DRD/parkinsonism patients. These findings on DRD indicate that the nigrostriatal DA neurons may be most susceptible to the decreases in GCH1 activity, BH4 level, TH activity, and DA level, and that DRD is the DA deficiency without neuronal death in contrast to juvenile parkinsonism or Parkinson's disease with DA cell death.
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PMID:Molecular genetics of dopa-responsive dystonia. 1066 62

Parkinson's disease (PD), a neurological disease suited to gene therapy, is biochemically characterized by a severe decrease in the dopamine content of the striatum. One current strategy for gene therapy of PD involves local production of dopamine in the striatum achieved by inducing the expression of enzymes involved in the biosynthetic pathway for dopamine. We previously showed that the coexpression of tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), using two separate adeno-associated virus (AAV) vectors, resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine-lesioned parkinsonian rats, compared with the expression of TH alone. Not only levels of TH and AADC but also levels of tetrahydrobiopterin (BH4), a cofactor of TH, and GTP cyclohydrolase I (GCH), a rate-limiting enzymes for BH4 biosynthesis, are reduced in parkinsonian striatum. In the present study, we investigated whether transduction with separate AAV vectors expressing TH, AADC, and GCH was effective for gene therapy of PD. In vitro experiments showed that triple transduction with AAV-TH, AAV-AADC, and AAV-GCH resulted in greater dopamine production than double transduction with AAV-TH and AAV-AADC in 293 cells. Furthermore, triple transduction enhanced BH4 and dopamine production in denervated striatum of parkinsonian rats and improved the rotational behavior of the rats more efficiently than did double transduction. Behavioral recovery persisted for at least 12 months after stereotaxic intrastriatal injection. These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD.
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PMID:Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, and GTP cyclohydrolase I for gene therapy of Parkinson's disease. 1094 65

The underlying cause of the selective death of the nigral dopaminergic neurons in Parkinson's disease is not fully understood. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of dopamine and nitric oxide. Because BH4 contributes to the syntheses of these two potential oxidative stressors and also undergoes autoxidation, thereby producing reactive oxygen species, it was possible that BH4 may play a role in the selective vulnerability of dopaminergic cells. BH4 given extracellularly was cytotoxic to catecholamine cells CATH. a, SK-N-BE(2)C, and PC12, but not to noncatecholamine cells RBL-2H3, CCL-64, UMR-106-01, or TGW-nu-1. This was not caused by increased dopamine or nitric oxide, because inhibition of their syntheses did not attenuate the damage and BH4 did not raise their cellular levels. Dihydrobiopterin and biopterin were not toxic, indicating that the fully reduced form is responsible. The toxicity was caused by generation of reactive oxygen species, because catalase, superoxide dismutase, and peroxidase protected the cells from the BH4-induced demise. Furthermore, thiol agents, such as reduced glutathione, dithiothreitol, beta-mercaptoethanol, and N-acetylcysteine were highly protective. The BH4 toxicity was initiated extracellularly, because elevation of intracellular BH4 by sepiapterin did not result in cell damage. BH4 was spontaneously released from the cells of its synthesis to a large extent, and the release was not further enhanced by calcium influx. This BH4-induced cytotoxicity may represent a mechanism by which selective degeneration of dopaminergic terminals and neurons occur.
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PMID:Tetrahydrobiopterin is released from and causes preferential death of catecholaminergic cells by oxidative stress. 1095 58

Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. TPH belongs to the family of the aromatic amino acid hydroxylases, including phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict requirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). 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. Although structural information about TPH is not yet available, the high sequence homology between the three mammalian hydroxylases, notably at the catalytic domains, and the similarity of the reactions that they catalyze, indicate that they share a similar 3D-structure and a common catalytic mechanism. Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH. This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines. The interactions of these ligands with the enzyme are discussed focusing on the physiological and pharmacological regulation of serotonin biosynthesis, notably by tryptophan supplementation therapy and substitution therapy with tetrahydrobiopterin analogues (positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinson's disease patients (enzyme inhibition).
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PMID:A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. 1147 42


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