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)

This article reviews the mechanism of dopamine delivery in the CNS in order to determine the optimal set of genes for effective gene therapy in Parkinson's disease (PD). Systematic neurobiological investigation of the biochemical steps has revealed that tyrosine hydroxylase (TH), which has been used in earlier studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1) is present. Transduction of the gene for GTP cyclohydrolase I, the first and rate-limiting step in BH1 synthesis, along with the TH gene, generated cells that are capable of producing L-DOPA spontaneously both in vitro and in vivo. When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback inhibition by the end product, dopamine, on TH activity resulted. To circumvent this problem, we employed a complementary strategy. Gene transfer of the vesicular monoamine transporter was combined with AADC and produced genetically modified cells that can convert L-DOPA to dopamine and store it for gradual release. This approach provided a means to regulate final dopamine delivery by controlling precursor doses and to achieve more sustained delivery of dopamine. Our investigation into determining the genes necessary for optimal dopamine delivery has been facilitated by in vivo biochemical assays using microdialysis. This technique has provided us with a clear and quantitative tool to compare the effects of various genes involved in dopamine synthesis and processing.
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PMID:Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models. 1143 52

In animal models of Parkinson's disease, gene transfer of aromatic L-amino acid decarboxylase (AADC) leads to an increase in the capacity of the striatum to decarboxylate exogenous L-DOPA. However, the functional effects of enhanced L-DOPA to dopamine conversion have not been explored. Here, we show that following adeno-associated virus (AAV)-AADC transduction, the transgenic AADC is able to decarboxylate exogenous L-DOPA more efficiently so that a dose of L-DOPA ineffective before gene transfer elicits a motor asymmetry (rotational behavior) following gene transfer. Furthermore, rotation scores showed a strong correlation with AADC activity in the lesioned striatum, thus allowing for behavioral screening of successful gene transfer in the brain. In animals receiving AAV2-AADC, dopamine production was restored to 50% of normal levels 12 weeks after the infusion. Microdialysis experiments demonstrated an in vivo enhanced conversion of L-DOPA to dopamine, but no storage capacity as dopamine was released to the extracellular space in a continuous, nonregulated fashion. In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment.
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PMID:Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats. 1159 35

Historically, 3,4-dihydroxyphenylalanine (DOPA) has been considered to be an inert amino acid that alleviates the symptoms of Parkinson's disease by its conversion to dopamine via the enzyme aromatic L-amino acid decarboxylase. In contrast to this generally accepted idea, we propose that DOPA itself is a neurotransmitter and/or neuromodulator in addition to being a precursor of dopamine. Several criteria such as synthesis, metabolism, active transport, existence, physiological release, competitive antagonism and physiological or pharmacological responses must be satisfied before a compound is accepted as a neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in its involvement in baroreflex neurotransmission.
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PMID:Is DOPA a neurotransmitter? 1208 31

Recent developments in viral vectors capable of providing high levels of long-term transgene expression in the brain have led to the pursuit of two strategies in gene therapy for the treatment of Parkinson's disease (PD). One is the local production of dopamine in the striatum achieved by inducing the expression of dopamine-synthesizing enzymes. Three enzymes are necessary for efficient dopamine synthesis: tyrosine hydroxylase (TH) converts tyrosine to L-DOPA, aromatic L-amino acid decarboxylase (AADC) then converts L-DOPA to dopamine, and guanosine triphosphate cyclohydrolase I (GCH) is the rate-limiting enzyme for the synthesis of TH co-factor tetrahydrobiopterine. We have previously demonstrated that transduction with separate adeno-associated virus (AAV) vectors expressing TH, AADC, and GCH is effective in reducing motor abnormalities in 6-hydroxydopamine-lesioned rats and in MPTP-treated monkeys. Behavioral recovery persisted for at least 18 months after intrastriatal injection in parkinsonian rats. In MPTP monkeys, the amelioration of motor abnormalities was remarkable on the contralateral side, accompanied by robust transgene expression and elevated dopamine synthesis in the AAV-injected putamen. The second strategy entails the expression of neurotrophic factors or brain vesicular monoamine transporter in the striatum or the substantia nigra to slow the degeneration of dopamine neurons. Gene therapy using viral vectors offers a promising approach in the treatment of PD patients.
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PMID:[Gene therapy for Parkinson's disease: studies in animal models]. 1223 25

It has recently been reported that the human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme), but not for tyrosine hydroxylase (TH; the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH; the first-step serotonin synthesizing enzyme). These AADC (+)/TH(-)/TPH(-) neurons are named D-neurons. AADC is also the rate-limiting synthesizing enzyme of phenylethylamine (PEA). Although the functions of striatal D-neurons are yet unclear, their functions were discussed in the present review based on recent findings in the literature. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors, including L-dopa or droxidopa (L-threo-DOPS), and by converting them to dopamine (DA) or noradrenaline (NA), respectively. Because the nucleus accumbens is one of the brain regions involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration. Further studies should be conducted to elucidate the functions of this unique cell group in the human striatum.
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PMID:[Human striatal D-neurons and their significance]. 1237 66

It has recently been reported that the human corpus striatum, especially its ventral part, named as the nucleus accumbens, contains numerous non-monoaminergic aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme) neurons (D-neurons). D-neurons are the neurons immunoreactive for AADC but not immunoreactive for dopamine or serotonin. They lack the first-step monoamine synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. AADC is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons might participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. As the nucleus accumbens is one of the brain regions that are involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration.
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PMID:[Localization of non-monoaminergic aromatic L-amino acid decarboxylase neurons (D-neurons) in the human striatum and their functional significance]. 1255 14

Historically, 3,4-dihydroxyphenylalanine (DOPA) has been believed to be an inert amino acid that alleviates the symptoms of Parkinson's disease by its conversion to dopamine via the enzyme aromatic L-amino acid decarboxylase. In contrast to this generally accepted idea, we propose that DOPA itself is a neurotransmitter and/or neuromodulator, in addition to being a precursor of dopamine. Several criteria, such as synthesis, metabolism, active transport, existence, physiological release, competitive antagonism, and physiological or pharmacological responses, must be satisfied before a compound is accepted as a neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in its involvement mainly in baroreflex neurotransmission in the lower brainstem and in delayed neuronal death by transient ischemia in the striatum and the hippocampal CA1 region of rats.
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PMID:L-3,4-Dihydroxyphenylalanine as a neurotransmitter candidate in the central nervous system. 1255 86

Benserazide is commonly used for Parkinson's disease in combination with L-DOPA as a peripheral aromatic L-amino acid decarboxylase (AADC) inhibitor. However, recent studies using intact animals indicate that benserazide acts also in the central nervous system. We determined the influence of benserazide on the central AADC activity in rats with dopaminergic denervation and observed changes in extracellular dopamine (DA) levels after benserazide and L-DOPA administration. First, using in vivo microdialysis technique, we measured extracellular DA levels in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats treated with benserazide and L-DOPA. Second, we measured AADC activity in the striatal tissues after benserazide administration. Although administration of 5, 10 and 50 mg/kg benserazide to 6-OHDA-lesioned rats showed an identical increase in exogenous L-DOPA-derived extracellular DA levels, the time to reach the peak DA levels were significantly prolonged by benserazide dose-dependently. The AADC activity in the denervated striatal tissues showed a significant decrease by 10 mg/kg and 50 mg/kg benserazide. These results suggest that benserazide reduces the central AADC activity in the striatum of rats with nigrostriatal denervation, which leads to changes in the metabolism of exogenous L-DOPA. Central activity of AADC inhibitors should be taken into consideration when they are used both in experimental and clinical studies on Parkinson's disease.
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PMID:Effects of benserazide on L-DOPA-derived extracellular dopamine levels and aromatic L-amino acid decarboxylase activity in the striatum of 6-hydroxydopamine-lesioned rats. 1270 59

The human striatum, especially its ventral part, the nucleus accumbens (Acc), contains numerous nonmonoaminergic aromatic L-amino acid decarboxylase (AADC) [=dopa decarboxylase (DDC)] neurons (D-neurons). AADC is the second-step synthesizing enzyme for monoamines and is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by taking up monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. Although previous studies have shown that AADC activity was elevated in the striatum of drug-naive schizophrenia, the number of striatal D-neurons was reduced in autopsy brains of schizophrenia. It is unclear whether or not such reduction of striatal D-neurons implies downregulation. Possible pluripotentiality of D-neurons, including compensatory functions against aging and degeneration, was discussed based on recent published works.
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PMID:Significance of human striatal D-neurons: implications in neuropsychiatric functions. 1509 49

AAV vectors are considered to be promising gene-delivery vehicles for gene therapy, because they are derived from non-pathogenic virus, efficiently transduce non-dividing cells, and cause long-term gene expression. Appropriate AAV serotypes are utilized depending on the type of target cells; e.g., neurons are efficiently transduced with AAV2 and AAV5 vectors, and an AAV1 vector is most suitable for muscles. Among various neurological disorders, Parkinson's disease (PD) is one of the most appropriate candidates of gene therapy. PD is a progressive neurodegenerative disorder that predominantly affects dopaminergic neurons in the substantia nigra. There are two major approaches to gene therapy of PD; i.e., 1) intrastriatal expression of dopamine (DA)-synthesizing enzyme genes, and 2) neuroprotection using the glial cell line-derived neurotrophic factor (GDNF) gene to prevent the disease progression. As for the initial step of clinical application, AADC (aromatic L-amino acid decarboxylase; the enzyme converting L-DOPA to DA) gene transfer in combination with oral administration of L-DOPA would be appropriate, since DA production can be regulated by the dose of L-DOPA. Preclinical studies are being conducted in MPTP-parkinsonian monkeys. AAV vector-mediated gene therapy would be feasible as a novel treatment of PD in the near future.
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PMID:[AAV vector-mediated gene transfer and its application to the nervous system]. 1515 79


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