UMLS:C0030567 - FACTA Search

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)

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

Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles.
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PMID:Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies. 961 21

The clinical distinction between dopa-responsive dystonia (DRD) and juvenile Parkinson's disease JPD) can pose a diagnostic challenge. Both conditions are dopa responsive. However, long-term L-dopa benefit is very different between the two. The difference in the prognosis is due to presence or absence of nigral cell loss. In JPD, there is degenerative nigral cell loss, whereas there are enzymatic defects in dopamine synthesis without cell loss in DRD. Mutations have been found in the GTP cyclohydrolase I (GCH-I) and tyrosine hydroxylase genes in DRD. As the discovered mutations are multiple and more are expected to be found, it is difficult to confirm or exclude DRD by mutation studies. Measurement of cerebrospinal fluid (CSF) neopterin will detect DRD from mutations in the GCH-I gene but not from mutations in tyrosine hydroxylase. The dopamine transporter (DAT) is a protein in the dopaminergic nerve terminals. (1R)-2beta-Carbomethoxy-3beta-(4-[123I]iodophenyl)tropane ([123I]beta-CIT) is a ligand for the DAT, and it was shown to be a useful nuclear imaging marker for neurons that degenerate in Parkinson's disease (PD). As DRD was shown to have a normal DAT without nigral cell loss in a postmortem study, we predicted that the DAT measured in vivo by nuclear imaging will be normal in DRD and will differentiate DRD from JPD. Therefore, we performed [123I]beta-CIT single-photon emission computed tomography ([123I]beta-CIT SPECT) in clinically diagnosed DRD, PD, and JPD, and examined whether DAT imaging can differentiate DRD from PD and JPD. We then examined whether DAT imaging can provide a screening tool for molecular genetic studies, by studying mutations in the candidate gene GCH-I and measuring CSF neopterin. Five females (4 from two families, and 1 sporadic) were diagnosed as DRD based on early-onset foot dystonia and progressive parkinsonism beginning at ages 7 to 12. All patients were functioning normally on L-dopa 100 to 250 mg/day for up to 8 years. SPECT imaging was obtained after intravenous injection of [123I]beta-CIT; 15 healthy volunteers served as normal control, and 6 PD and 1 JPD as disease controls. [123I]beta-CIT striatal binding was normal in DRD, whereas it was markedly decreased in PD and JPD. Gene analysis showed a novel nonsense mutation in the GCH-I gene in one family. No mutation was found in the other family or in the sporadic case. CSF neopterin was markedly decreased in the 4 tested patients. [123I]beta-CIT SPECT is a sensitive method for probing the integrity of nigrostriatal dopaminergic nerve terminals. A normal striatal DAT in a parkinsonian patient is evidence for a nondegenerative cause of parkinsonism and differentiates DRD from JPD. Finding a new mutation in one family and failure to demonstrate mutations in the putative gene in other cases supports the usefulness of DAT imaging in diagnosing DRD.
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PMID:Dopamine transporter density measured by [123I]beta-CIT single-photon emission computed tomography is normal in dopa-responsive dystonia. 962 49

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients.
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PMID:Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease. 1245 Nov 30

Hereditary progressive dystonia with marked diurnal fluctuation/dopa-responsive dystonia (HPD/DRD) shows the considerable heterogeneity of clinical phenotypic expression and a dramatic sustained response to levodopa. The autosomal dominant HPD/DRD is caused by mutations in the gene coding GTP cyclohydrolase I (GCH I), the enzyme that catalyzes the first step in the biosynthesis of tetrahydrobiopterin. Previous studies suggested that normal [18F]Dopa positron emission tomography or [123I]beta-CIT single-photon emission computed tomography (SPECT) imaging, indicating intact structural integrity of nigrostriatal neurons, may be useful for differentiating HPD/DRD from clinically similar conditions such as juvenile Parkinson's disease with dystonia that have a considerably poorer prognosis. We here report a Korean family affected with HPD/DRD due to a novel missense mutation of the GCH I gene (T-->G mutation in exon 2), Met 137 Arg, which may change the conformation of the binding site of GCH I. The clinical features are considerably variable within the family. We documented normal striatal uptake of [123I]IPT, a dopamine transporter ligand with fast washout kinetics, in our patients by using SPECT. This method can be helpful in diagnosing HPD/DRD in uncertain cases.
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PMID:A novel missense mutation of the GTP cyclohydrolase I gene in a Korean family with hereditary progressive dystonia/dopa-responsive dystonia. 1516 67

Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease.
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PMID:Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors. 1565 29

Neural stem cells (NSCs) of the central nervous system (CNS) recently have attracted a great deal of interest not only because of their importance in basic research on neural development, but also in terms of their therapeutic potential in neurological diseases, such as Parkinson's disease (PD). To examine if genetically modified NSCs are a suitable source for the cell and gene therapy of PD, an immortalized mouse NSC line, C17.2, was transduced with tyrosine hydroxylase (TH) gene and with GTP cyclohydrolase 1 (GTPCH1) gene, which are important enzymes in dopamine biosynthesis. The expression of TH in transduced C17.2-THGC cells was confirmed by RT-PCR, Western blot analysis, and immunocytochemistry, and expression of GTPCH1 by RT-PCR. The level of L-DOPA released by C17.2-THGC cells, as determined by HPLC assay, was 3793 pmol/10(6) cells, which is 760-fold higher than that produced by C17.2-TH cells, indicating that GTPCH1 expression is important for L-DOPA production by transduced C17.2 cells. Following the implantation of C17.2-THGcC NSCs into the striata of parkinsonian rats, a marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats grafted with C17.2-THGC cells but not in the control rats grafted with C17.2 cells. These results indicate that genetically modified NSCs grafted into the brain of the parkinsonian rats are capable of survival, migration, and neuronal differentiation. Collectively, these results suggest that NSCs have great potential as a source of cells for cell therapy and an effective vehicle for therapeutic gene transfer in Parkinson's disease.
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PMID:Brain transplantation of neural stem cells cotransduced with tyrosine hydroxylase and GTP cyclohydrolase 1 in Parkinsonian rats. 1592 54

Parkinson disease is a neurodegenerative disease characterized by loss of midbrain dopaminergic neurons resulting in movement disorder. Neural stem cells (NSC) of the CNS have recently aroused a great deal of interest, not only because of their importance in basic research of neural development, but also for their therapeutic potential in neurological disorders. We have recently generated an immortalized human NSC cell line, HB1.F3, via retrovirus-mediated v-myc transfer. This line is capable of self-renewal, is multipotent, and expresses cell specific markers for NSC, ATP-binding cassettes transporter (ABCG2) and nestin. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1) in order to generate dopamine-producing NSC. The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of L-dihydroxyphenyl alanine in HPLC analysis. A marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats implanted with F3.TH.GTPCH cells, but not in control rats receiving F3 NSC. In the animals showing functional improvement, a large number of TH-positive F3.TH.GTPCH NSC were found at injection sites. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease.
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PMID:Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. 1670 45

Parkinson's disease is the second most common neurodegenerative disease. It is charaterized by a progressive loss of dopamine (DA) producing neurons in the midbrain, which result in a decline of DA innervations present in the forebrain, in particular, the striatum. The disease leads to appearance of motor symptoms involving akinesia/bradykinesia, gait disturbances, postural imbalance and tremor. Oral administration of L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor of DA, provides very good symptomatic relief, but this intermittent and pharmacological treatment is compromised by severe side effects, such as the appearance of abnormal involuntary movements. Viral vector-mediated direct gene transfer techniques are currently being explored in order to provide continuous and stable synthesis of DA in the brain. This review focuses on the basic idea of DA replacement, first describing the enzymatic machinery important for DA synthesis and secondly the various alternative strategies pursued in several laboratories. The DOPA delivery strategy, based on the co-transduction of tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) genes, has been shown to be a powerful approach providing a robust behavioral recovery and reversal of side effects of the pulsatile administration of L-DOPA medication. The DA delivery strategy, on the other hand, aims at triple transduction of the TH, GCH1 and aromatic amino-acid decarboxylase (AADC) enzymes, and thereby provide a higher rate of conversion of DOPA to DA. Finally, transduction of AADC alone has been proposed as a means to improve the conversion of peripherally administered L-DOPA. As the basic scientific rationale behind these strategies are well understood and the results of the animal experiments are very encouraging, we are now entering into an exciting phase with increasing momentum toward the first clinical applications using this experimental therapy in patients suffering from PD.
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PMID:Restoration of the striatal dopamine synthesis for Parkinson's disease: viral vector-mediated enzyme replacement strategy. 1743 Jan 30

In vivo gene transfer using viral vectors is an emerging therapy for neurodegenerative diseases with a clinical impact recently demonstrated in Parkinson's disease patients. Recombinant adeno-associated viral (rAAV) vectors, in particular, provide an excellent tool for long-term expression of therapeutic genes in the brain. Here we used the [(11)C]raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [(11)C]raclopride binding in hemiparkinsonian rats. Importantly, we show in vivo by microPET imaging and postmortem by classical binding assays performed in the very same animals that the changes in [(11)C]raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D(2) receptors, providing evidence for reconstitution of a functional pool of endogenous dopamine in the striatum. Moreover, the extent of the normalization in this non-invasive imaging measure was highly correlated with the functional recovery in motor behavior. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as an in vivo imaging technique to follow TH + GCH1 gene therapy in PD patients and provide an additional objective measure to a potential clinical trial using rAAV vectors to deliver l-3,4-dihydroxyphenylanaline in the brain.
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PMID:Positron emission tomography imaging demonstrates correlation between behavioral recovery and correction of dopamine neurotransmission after gene therapy. 1919 1

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