Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mRNA levels encoding for the enzyme glutamate decarboxylase (GAD65) were measured by computerized image analysis after in situ hybridization histochemistry in the striatum and pallidum of normal and MPTP-treated squirrel monkeys. At striatal level, GAD65 mRNA labeling in MPTP-treated monkeys was primarily increased in the dorsolateral sector of the putamen. At pallidal level, the intensity of GAD65 mRNA labeling in single neurons was increased in the internal but not the external segment of the pallidum of MPTP-treated monkeys. The regulation of GAD65 mRNA levels in the striatum and internal segment of the pallidum suggest an important role for this enzyme in the regulation of GABAergic functions in basal ganglia.
Brain Res Mol Brain Res 1994 Sep
PMID:Glutamate decarboxylase (GAD65) mRNA levels in the striatum and pallidum of MPTP-treated monkeys. 780 34

We have examined the ultrastructure of the striatum in squirrel monkeys 1-5 d after a single sc injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2.5 mg/kg. One untreated monkey served as control. We expected to find a dense degeneration of the dopamine terminals, but found instead that the main abnormality consisted of a focal vacuolation of the tissue, perhaps related to the striosome/matrix mosaic of the neostriatum. The vacuolation involved not only terminals, but also other parts of the neuropil. The severity of the destructive process increased from d 1-5. We conclude that MPP+, the toxic metabolite of MPTP, may gain access to the neuropil, either before or after its active uptake into and subsequent destruction of the dopamine terminals. In the present study, abnormalities were observed simultaneously in the striatum and substantia nigra as early as 24 h after MPTP administration. It is, however, possible that the time-course might differ between the two locations with even shorter time intervals or changes in dosage of MPTP.
Mol Neurobiol
PMID:Evolution of nerve fiber degeneration in the striatum in the MPTP-treated squirrel monkey. 788 93

Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitrary subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.
Brain Res Mol Brain Res 1994 Mar
PMID:Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon. 791 4

1. Intracerebral injection of the oxidative metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridine (MPP+), into the substantia nigra of adult rats resulted in a lesion at the injection site. 2. Using autoradiography, we localized specific [125I]CGP 42112 binding that was not recognized by angiotensin II or angiotensin II AT1 or AT2 receptor-selective ligands. 3. Our results suggest that [125I]CGP 42112 may be binding to activated microglia that appear at the lesion site.
Cell Mol Neurobiol 1994 Feb
PMID:[125I]CGP 42112 reveals a non-angiotensin II binding site in 1-methyl-4-phenylpyridine (MPP+)-induced brain injury. 795 64

A synaptic vesicle amine transporter cDNA, termed hSVAT, has been isolated by the reverse transcription and polymerase chain reaction (PCR) technique from human substantia nigra and subsequent screening of a human substantia nigra library. The hSVAT sequence obtained is highly homologous to the rat SVAT sequence (92% homology) and is essentially identical to the human sequence identified recently by Surratt and colleagues [33]. This labelled hSVAT cDNA detected a single band (approximately 5.0 kb) when used as a probe for Northern analysis of human nigral RNA extract. In situ hybridization studies using hSVAT specific antisense oligonucleotides showed a strong hybridization signal concentrated over the cells of the substantia nigra pars compacta. This cDNA sequence when expressed in chinese hamster ovary (CHO) cells conferred resistance to MPP+ the toxic metabolite of MPTP and cells containing it accumulated dopamine.
Brain Res Mol Brain Res 1994 Aug
PMID:The molecular cloning and expression of a human synaptic vesicle amine transporter that suppresses MPP+ toxicity. 798 57

In order to compare the recovery capacity of the nigrostriatal system between adult and old mice, MPTP hydrochloride was administered to 48 BL/C57 male mice, which were sacrificed 24 h or 10 d after the second dose. The animals were divided into four groups, based on age (adult or old) and moment of sacrifice (24 h or 10 d). The detailed morphology of the neurons and the cellular processes of the substantia nigra pars compacta and the striatum were studied using the Golgi method. Immunostaining with a polyclonal glial fibrillary acidic protein antiserum using the peroxidase-antiperoxidase technique was performed to study the glial response. Striatal catecholamines were determined to correlate the biochemical data with the morphological changes. Significant neuronal changes of cellular processes were observed in substantia nigra pars compacta from all MPTP-treated mice, consisting of swelling and distortion of cellular bodies, discontinuous thickness, and nodulations of dendrites with baded aspect. Axons showing focal swelling and nodulations were also found in the neuropil of silver impregnated striata. Marked gliosis with reactive astrocytes in substantia nigra and striatum from all the old treated mice was found. Recovery was only observed in adult mice sacrificed 10 d after withdrawal. At this time, all the old MPTP-treated mice showed marked neuronal changes and a persistent marked gliosis. As expected, 24 h after the MPTP treatment, a marked depletion of dopamine and its metabolites was found in all the animals; at 10 d, the depletion was partially reversed in the adult group. These data correlate well with the observed morphological changes. Our results suggest that, in mice, deterioration of dendritic and axonal neuropil constitutes a significant causal factor of the MPTP neurotoxicity. These features are related to the age of the animals and the integrity of the plasticity phenomena, which appear to be altered in old mice.
Mol Chem Neuropathol
PMID:Plasticity of the nigrostriatal system in MPTP-treated mice. A biochemical and morphological correlation. 810 34

MPTP is a murine homolog of the human T-cell protein tyrosine phosphatase (PTPase) and the rat PTP-S enzyme. Enzymatic activity of this ubiquitously expressed protein was demonstrated in immunoprecipitates from NIH 3T3 cells and in recombinant protein overexpressed in bacteria. Expression of beta-galactosidase-MPTP MPTP chimeric proteins in COS1 cells identified a nuclear localization signal at the carboxyl terminus of the MPTP that was sufficient to direct beta-galactosidase as well as a tagged version of the MPTP to the nucleus. Deletion analysis of amino acids within the nuclear targeting signal showed that this sequence does not conform to the bipartite type of nuclear localization signals. Furthermore, it was shown that the steady-state levels of MPTP RNA fluctuate in a cell cycle-specific manner. On the basis of these experiments, we discuss the possible function of MPTP in the cell cycle and other nuclear processes.
Mol Cell Biol 1994 May
PMID:Nuclear localization and cell cycle regulation of a murine protein tyrosine phosphatase. 816 59

The number of nigral dopamine neurons and striatal dopamine levels are reduced by 70% in the adult weaver mutant mouse (wv/wv), whereas these parameters are essentially unchanged in the heterozygote (wv/+). We hypothesized that the remaining nigral dopamine neurons and/or striatal dopamine levels in the weaver would be less sensitive to neurotoxic or dopamine-depleting agents and that nigral neurons in the heterozygote would be more vulnerable. Mice were treated with the dopaminergic neurotoxin MPTP using different injection schedules and also with reserpine. There was a similar percent decrease in striatal DA in weavers and heterozygotes compared to normal mice after these treatments. We did observe a gene-dose-related lethality to the highest dose treatment with MPTP. These results suggest that the remaining dopaminergic neurons in the weaver are not different from those in normal mice in their capacity to respond to MPTP and reserpine.
Mol Chem Neuropathol 1993 Dec
PMID:Dopamine-depleting effects of MPTP and reserpine in weaver mutant mice. 817 26

GM1 has been reported to promote sprouting of dopaminergic mesencephalic neurons when administered at the time of MPTP treatment. Owing to its potential clinical significance, we evaluated behavioral effects of GM1 treatment in three Cebus apella monkeys with a persistent hemiparkinsonian syndrome after 20-22 mo of an intracarotid infusion of MPTP. MPTP monkeys compared with normal ones presented difficulty in solving motor cognitive tests and reversal of circling activity after apomorphine treatment. Monkeys were treated during 3 wk with daily saline, followed by 4 wk with GM1 (20 mg/kg, im). Neither during saline nor GM1 treatment, nor 30 d afterwards, did the animals improve their performances nor did the apomorphine tests reveal significant changes in circling behavior. These results are discussed in terms of their possible implications for Parkinson disease treatment.
Mol Chem Neuropathol 1994 Jan
PMID:Long-term MPTP-treated monkeys are resistant to GM1 systemic therapy. 817 73

Protein tyrosine phosphatases (PTPs), together with protein tyrosine kinases (PTKs), are involved in the regulation of cell activation, growth, and differentiation. To further elucidate the fine tuning of cell growth and differentiation through tyrosine phosphorylation, we tried to isolate mouse receptor-type PTP (RPTP) cDNA clones by screening mouse brain cDNA libraries with mouse CD45 PTP domain probes under reduced-stringency conditions. Characterization of isolated cDNA clones for RPTP showed that the cytoplasmic region contains two tandem repeats of PTP domain of about 230 amino acids with intrinsic phosphatase activity. The extracellular region was composed of immunoglobulin (Ig)-like domains and fibronectin type III (FN-III)-like domains. The gene was highly homologous to human PTP delta (HPTP delta) and thus was named MPTP delta (murine counterpart of HPTP delta). The MPTP delta gene appeared to generate at least three species of mRNA, which differ in the composition of the extracellular domain: type A, one Ig-like and four FN-III-like domains; type B, one Ig-like and eight FN-III-like domains; and type C, three Ig-like and eight FN-III-like domains. Interestingly, the 5' untranslated region and the leader peptide of types A and B were completely different from those of type C. Northern (RNA) blot analysis demonstrated that brain, kidney, and heart cells express three mRNA species of about 7 kb. Antibody directed against part of the extracellular domain of type A MPTP delta recognized a 210-kDa protein in brain and kidney lysates. In situ hybridization of brain samples revealed that MPTP delta mRNA is present in the hippocampus, thalamic reticular nucleus, and piriform cortex, where some Src family PTKs have been also demonstrated to exist. Although MPTP delta mRNA was not detected in lymphoid tissues, all of the pre-B-cell lines tested and one of three B-cell lines tested expressed MPTP delta mRNA, whereas antibody-producing B-cell hybridomas and T-cell and macrophage lines did not. Finally, the MPTP delta locus was tightly linked to the brown (b) locus on mouse chromosome 4.
Mol Cell Biol 1993 Sep
PMID:MPTP delta, a putative murine homolog of HPTP delta, is expressed in specialized regions of the brain and in the B-cell lineage. 835 97


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