Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current approaches to gene therapy of CNS disorders include grafting genetically modified autologous cells or introducing genetic material into cells in situ using a variety of viral or synthetic vectors to produce and deliver therapeutic substances to specific sites within the brain. Here we discuss issues related to the application of ex-vivo and in-vivo gene therapies as possible treatments for Parkinson's disease. Autologous monkey fibroblasts engineered ex-vivo to express tyrosine hydroxylase were grafted into MPTP-treated monkeys and found to express for up to 4 months. Adeno-associated (AAV) viral vectors expressing beta-galactosidase or tyrosine hydroxylase were introduced into monkey brains to determine the extent of infection and the types of cells infected by the vector at 21 days and 3 months. Gene expression was detected at both time points and was restricted to neurons in the striatum. These experiments demonstrate that two different approaches can be used to deliver proteins into the CNS. However, further technological advances are required to optimize gene delivery, regulation of gene expression, and testing in appropriate functional models before gene therapy can be considered for treating human disease.
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PMID:Practical aspects of the development of ex vivo and in vivo gene therapy for Parkinson's disease. 912 64

Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and beta-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.
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PMID:Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase. 915 52

The enzyme tyrosinase is indispensable for pigmentation and the gene is expressed mainly in pigment cells. Regulatory elements, at -12 to -15 kb (enhancer) and within the 270 bp directly upstream of the transcription start site, have been described recently and their importance demonstrated in transgenic experiments. We were interested in tyrosinase promoter activity during development and used beta-galactosidase as reporter gene. Transgenic mice were generated carrying a tyrosinase-lacZ fusion gene, containing 6.1 kb of tyrosinase 5' sequences. In transgenic embryos, beta-galactosidase activity was detected along the entire neural tube, with the most prominent expression in the developing telencephalon, and also in the adult brain. Equivalent expression was observed in the developing retina. Tyrosinase protein was identified in embryonic and adult brain, but no DOPAoxidase or tyrosine hydroxylase activity was detected. From our results we conclude that 1) tyrosinase protein is present in embryonic and adult mouse brain and 2) the tyrosinase promoter can direct expression of a reporter gene to pigment cells and neural tissues.
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PMID:Regulation of the tyrosinase promoter in transgenic mice: expression of a tyrosinase-lacZ fusion gene in embryonic and adult brain. 926 2

Transcriptional regulatory elements capable of directing transgene expression to individual cells are powerful tools for manipulating a given CNS circuit. Delineating these elements via traditional transgenic analysis is both costly and labor intensive. Here we have used the rat tyrosine hydroxylase (TH) promoter as a model to describe and validate the use of founder animals for systematic promoter studies. No significant differences were found when data obtained from founder animals expressing a 6.0 kb TH promoter directing LacZ were compared with animals derived from an analogous transgenic line. Subsequent studies with founder animals expressing beta-galactosidase directed by various lengths of rat TH promoter revealed different patterns of expression. Specifically, a locus coeruleus regulatory domain was localized between 3.4 and 6.0 kb of the rat TH promoter, a hypothalamic regulatory domain between 2.5 and 3.4 kb and a brainstem regulatory domain between 0.8 and 6.0 kb. At least one element of a midbrain specific regulatory domain was within 2.5 kb of the transcriptional start site. Olfactory bulb specific elements however appeared to reside outside of the sequences tested. Specific patterns of ectopic gene expression were also observed suggesting the presence of negative regulatory elements. Thus, TH appears to be regulated in a complex modular fashion by both positive and negative regulatory elements. Taken together, this study demonstrates the feasibility and reliability of founder analysis for promoter studies of genes expressed in complex spatial and temporal patterns.
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PMID:Identification of cell type-specific promoter elements associated with the rat tyrosine hydroxylase gene using transgenic founder analysis. 940 15

Embryonic ventral midbrains from GFAP-lacZ transgenic mice were xenografted into the dopamine-depleted striata of adult rats. This transgenic line harbors a nuclear-targeted bacterial beta-galactosidase (beta-gal) reporter gene under transcriptional control of the human glial fibrillary acidic protein (GFAP) promoter sequence. Five weeks post-transplantation, graft-derived astrocytes and dopaminergic neurons were visualized by dual immunocytochemistry for beta-gal and tyrosine hydroxylase (TH), respectively. This report describes the advantages associated with the use of GFAP-lacZ transgenic mice to study astrocyte fate in embryonic neural grafts.
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PMID:Use of GFAP-lacZ transgenic mice to determine astrocyte fate in grafts of embryonic ventral midbrain 947 41

Embryonic ventral midbrains from GFAP-lacZ transgenic mice were xenografted into the dopamine-depleted striata of adult rats. This transgenic line harbors a nuclear-targeted bacterial beta-galactosidase (beta-gal) reporter gene under transcriptional control of the human glial fibrillary acidic protein (GFAP) promoter sequence. Five weeks post-transplantation, graft-derived astrocytes and dopaminergic neurons were visualized by dual immunocytochemistry for beta-gal and tyrosine hydroxylase (TH), respectively. This report describes the advantages associated with the use of GFAP-lacZ transgenic mice to study astrocyte fate in embryonic neural grafts.
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PMID:Use of GFAP-lacZ transgenic mice to determine astrocyte fate in grafts of embryonic ventral midbrain. 949 89

The objective of the present study was to evaluate the expression of polysialic acid (PSA) and the cell adhesion molecule L1 during axonal regeneration and sprouting after injury to the adult rat brain. All animals received a complete lesion of the fimbria-fornix (FF). Grafts of nerve growth factor (NGF)- or beta-galactosidase (betaGal)-producing fibroblasts were placed in the FF lesion cavity and induced septohippocampal cholinergic regeneration or sympathetic tyrosine hydroxylase (TH)-positive sprouting, respectively. Cholinergic regeneration was evaluated from 2 to 8 weeks following grafting of NGF-producing fibroblasts in the FF lesion cavity. In the graft area, choline acetyltransferase (ChAT)-positive fibers expressed L1 and PSA. Once cholinergic axons reached the hippocampal formation (HF), they no longer expressed L1 or PSA. Eight weeks after a lesion of the FF and transplantation of betaGal-producing fibroblasts, TH-positive fibers sprouted in the denervated HF and expressed L1 but not PSA. At the zone of reactive gliosis, PSA but not L1 expression was increased following a lesion of the FF and transplantation of NGF- or betaGal-producing fibroblasts. In animals that received a graft of NGF-producing fibroblasts in the FF lesion cavity, numerous ChAT-positive axons were observed along these areas rich in PSA and reactive astrocytes. Taken together, these results suggest that the expression of PSA and L1 is upregulated on regenerating cholinergic axons during axonal elongation and downregulated upon target innervation. In contrast, TH-positive fibers that sprout in the denervated HF express and maintain their expression of L1. Finally, the expression of PSA in the area of reactive gliosis may contribute to a permissive environment for axonal regrowth.
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PMID:Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation. 972 97

An adeno-associated virus (AAV) vector, expressing genes for human tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), demonstrated significantly increased production of dopamine in 293 (human embryonic kidney) cells. This bicistronic vector was used to transduce striatal cells of six asymptomatic but dopamine-depleted monkeys which had been treated with the neurotoxin MPTP. Striatal cells were immunoreactive for the vector-encoded TH after stereotactic injection for periods up to 134 days, with biochemical effects consistent with dopamine biosynthetic enzyme expression. A subsequent experiment was carried out in six more severely depleted and parkinsonian monkeys. Several TH/aadc-treated monkeys showed elevated levels of dopamine near injection tracts after 2.5 months. Two monkeys that received a beta-galactosidase expressing vector showed no change in striatal dopamine. Behavioral changes could not be statistically related to the vector treatment groups. Toxicity was limited to transient fever in several animals and severe hyperactivity in one animal in the first days after injection with no associated histological evidence of inflammation. This study shows the successful transfection of primate neurons over a period up to 2.5 months with suggestive evidence of biochemical phenotypic effects and without significant toxicity. While supporting the idea of an in vivo gene therapy for Parkinson's disease, more consistent and longer lasting biochemical and behavioral effects will be necessary to establish the feasibility of this appraoch in a primate model of parkinsonism.
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PMID:In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. 974 62

Levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, are known to be upregulated in specific brain regions by chronic administration of drugs of abuse. Chronic morphine administration increases TH levels in the locus coeruleus and ventral tegmental area, whereas chronic cocaine administration increases TH levels in the ventral tegmental area only. While such upregulation of TH has been related to behavioral effects of the drugs, the mechanism underlying these adaptations has remained controversial. To study the possibility that upregulation of TH occurs at the transcriptional level, we investigated the effect of chronic morphine or cocaine treatment on the activity of the TH gene promoter (9.0 kb), coupled to the LacZ reporter gene, in transgenic mice. These TH9.0-LacZ mice have been shown to exhibit correct tissue-specific expression and regulation of the reporter gene. We show here that chronic (but not acute) exposure of the TH9.0-LacZ mice to morphine increases the expression of beta-galactosidase (which is encoded by the LacZ gene) in the locus coeruleus by twofold compared with sham-treated mice. In contrast, beta-galactosidase expression in the ventral tegmental area was decreased 20-25% by chronic morphine and unaffected by chronic cocaine administration. Similar results were obtained after analysis of TH mRNA levels in these brain regions by in situ hybridization. These results suggest that chronic morphine upregulates TH expression via transcriptional mechanisms in the locus coeruleus but by post-transcriptional mechanisms in the ventral tegmental area.
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PMID:Regulation of tyrosine hydroxylase promoter activity by chronic morphine in TH9.0-LacZ transgenic mice. 982 54

Adenovirus-mediated transfer of the leptin gene causes severe hyperleptinemia with rapid disappearance of visible body fat. To determine if this dramatic lipopenic action is mediated by neurotransmitted signals from the central nervous system, we transplanted the right epididymal fat pad of normal rats to the anterior abdominal wall. Four weeks later, rats were infused with either adenovirus-leptin cDNA (AdCMV-leptin) or adenovirus-beta-galactosidase (AdCMV-beta-gal). Eight days later, plasma leptin averaged 23 +/- 12 ng/ml in the former and 1.2 +/- 0.4 ng/ml in the latter. The fat transplant was intact in all 4 AdCMV-beta-gal-infused rats but had disappeared in all 4 hyperleptinemic rats. Tyrosine hydroxylase staining of the fat pad remnant was negative, excluding regrowth of sympathetic nerves. Thus, the lipopenic action of severe hyperleptinemia on adipocytes is not mediated by neurotransmitters, but must have resulted either from direct action of leptin and/or from leptin-mediated neurohormones.
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PMID:Hyperleptinemia depletes fat from denervated fat tissue. 1040 21


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