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)

Human brain levels of glutathione (GSH), glutathione disulfide (GSSG), and vitamin E were measured in neurologically normal control patients and two groups of patients with neurodegeneration: those with Alzheimer's disease (AD), and AD with some features of Parkinson's disease (AD-PD). Control brain samples contained GSH levels more than 50 times higher than GSSG. The levels of GSH were highest in the caudate nucleus and lowest in the medulla. In patients with AD or AD-PD, hippocampal levels of GSH were significantly higher than controls. Patients with AD also demonstrated high GSH levels in the midbrain compared to normal. In contrast, patients with AD-PD did not have significantly elevated GSH levels in this site. GSSG levels were not significantly different in any brain region between controls and diseased patients. In control brains, the medulla had higher levels of vitamin E than any other brain region. The caudate nucleus had the lowest levels, which were about half the levels in the medulla. Control levels of vitamin E in the midbrain were about 18.8 micrograms/g. In AD patients the midbrain levels of vitamin E doubled to 42.3 micrograms/g. This doubling also occurred in AD-PD patients where midbrain vitamin E levels increased to 44.0 micrograms/g. These results may indicate that compensatory increases in GSH and vitamin E levels occur following damage to specific brain regions in patients with AD or AD-PD.
Mol Chem Neuropathol 1991 Jun
PMID:Alzheimer's and Parkinson's disease. Brain levels of glutathione, glutathione disulfide, and vitamin E. 195 64

1. The application of in situ hybridization histochemistry to the study of neuropeptide gene expression in human brain postmortem tissues is reviewed. We focus on neuropeptides preferentially expressed in hypothalamus and basal ganglia. 32P-labeled oligonucleotides were used as hybridization probes. 2. Autoradiography combined with computerized image analysis was used to visualize and quantify the hybridization signal. 3. Several criteria were considered in order to ascertain the specificity of the signal, including Northern analysis, use of heterologous probes, competition assays, and thermal stability of the hybrids. 4. In control human striatum high levels of hybridization signal were observed for somatostatin, neuropeptide Y, and preproenkephalin A mRNAs. In contrast, no detectable signal was observed with the cholecystokinin, arginine-vasopressin, and oxytocin probes in this area. In the hypothalamus high levels of oxytocin and arginine-vasopressin mRNAs were visualized in several nuclei. Preproenkephalin A and somatostatin mRNAs were also observed in this region, while cholecystokinin mRNA was not detected. 5. No significant correlations were found between the density of the hybridization signal and parameters such as postmortem delay, age, and gender in the population studied. 6. Finally, alterations of mRNA levels for some of these peptides were found in Parkinson's disease and Huntington's chorea striatal tissues. 7. These results show that in situ hybridization histochemistry can be used to examine at the microscopic level neuropeptide gene expression in postmortem materials.
Cell Mol Neurobiol 1990 Mar
PMID:The use of in situ hybridization histochemistry for the study of neuropeptide gene expression in the human brain. 233 44

[3H]Inositol 1,4,5-trisphosphate [( 3H]Ins-(1,4,5)P3) binding studies were done on the human brain obtained at autopsy. The specific [3H]Ins(1,3,4,5)P3 binding sites in the cerebral and cerebellar cortices consisted of a single component with a high affinity (Kd = 11.3 and 16.5 nM, Bmax = 0.8 and 6.4 pmol/mg protein, respectively). The binding of [3H]Ins(1,4,5)P3 was potently inhibited by Ins(1,4,5)P3, in a nanomolar concentration, while other inositol phosphates and inositol were either much less potent or did not inhibit binding. The binding sites for [3H]Ins(1,4,5)P3 were discretely localized and were in the order: cerebellum much greater than basal ganglia, cerebral cortex greater than rhinencephalon greater than diencephalon, mesencephalon. There was an age-related loss of [3H]Ins(1,4,5)P3 binding in the frontal cortex. In the brains of patients with Parkinson's disease, [3H]Ins(1,4,5)P3 binding sites were reduced by about 50% in the caudate nucleus, putamen, and pallidum, while there were no differences in the frontal cortex, as compared to findings in the age-matched controls. Our findings suggest that [3H]Ins(1,4,5)P3 binding sites are closely linked to neural elements in the human brain.
J Mol Neurosci 1989
PMID:Inositol 1,4,5-trisphosphate binding sites in the brain: regional distribution, characterization, and alterations in brains of patients with Parkinson's disease. 256 94

We have characterized and localized phorbol ester binding sites in human autopsied brains, using [3H]phorbol 12,13-dibutyrate ([3H]PDBu). When the tissue was homogenized in the absence of Ca2+ chelator (10 mM EGTA/2 mM EDTA), Scatchard analysis of the specific [3H]PDBu bindings to both particulate and soluble fractions yielded a single class of high-affinity binding site (Kd = 7.1 and 7.4 nM: Bmax = 45.4 and 3.1 pmol/mg protein, respectively). The particulate fraction retained the majority of [3H]PDBu binding (98% of total binding activity), while the soluble fraction was almost devoid of binding activity (2%). In the presence of Ca2+ chelator, more of the activity was found in the soluble fraction (30%). The binding of [3H]PDBu was potently inhibited by active phorbol esters and related diterpenes with Ki of nanomolar concentration but not by inactive ones. Diolein (OAG), a synthetic diacylglycerol, and polymixin B, an inhibitor of protein kinase C (PKC), inhibited the binding moderately (Ki = 5.8 and 1.3 microM, respectively). H-7, an inhibitor of PKC and cyclic nucleotides-dependent kinase, did not compete with [3H]PDBu for the binding sites (Ki greater than 100,000 nM). The regional distribution of specific [3H]PDBu binding in the human brain was rather uneven and resembled that of [3H]PDBu autoradiograms and PKC-like immunoreactivities in the rat brain. The binding capacities were generally in the order: rhinencephalon greater than basal ganglia greater than cerebral cortex greater than diencephalon greater than cerebellum greater than mesencephalon. Age-related loss of binding sites was observed in the prefrontal cortex of the subjects 33-81 years of age. In Parkinson's disease, the phorbol ester binding showed a significant reduction in the substantia nigra, caudate putamen, and pallidum, whereas it was unchanged in the prefrontal cortex and caudate nucleus of schizophrenics, when compared with the relevant controls.
J Mol Neurosci 1989
PMID:Phorbol ester binding sites in human brain: characterization, regional distribution, age-correlation, and alterations in Parkinson's disease. 264 64

1. Dopaminergic neurotransmission in brain is receiving increased attention because of its known involvement in Parkinson's disease and new methods for the treatment of this disorder and because of hypotheses relating several psychiatric disorders to abnormalities in brain dopaminergic systems. 2. Chemical assessment of brain dopamine metabolism has been attempted by measuring levels of its major metabolite, homovanillic acid (HVA), in cerebrospinal fluid, plasma, or urine. Because HVA is derived in part from dopamine formed in noradrenergic neurons, plasma levels and urinary excretion rates of HVA do not adequately reflect solely metabolism of brain dopamine. 3. Using debrisoquin, the peripheral contributions of HVA to plasma or urinary HVA can be diminished, but the extent of residual HVA formation in noradrenergic neurons is unknown. By measuring the levels of methoxy-hydroxyphenylglycol (MHPG) in plasma or of urinary norepinephrine metabolites (total MHPG in monkeys; the sum of total MHPG and vanillyl mandelic acid (VMA) in humans) along with HVA, it is possible to estimate the degree of impairment by debrisoquin of HVA formation from noradrenergic neuronal dopamine and thereby better assess brain dopamine metabolism. 4. This method was applied to a monkey before and after destruction of the nigrostriatal pathway by the administration of MPTP.
Cell Mol Neurobiol 1988 Jun
PMID:A new approach to biochemical evaluation of brain dopamine metabolism. 304 92

1. Nicotine, an important pharmacological component of cigarette smoke, is known to have significant effects on central nervous system (CNS) dopaminergic function. Although acute doses of nicotine have been shown to facilitate dopamine release, recent data indicate that chronic nicotine treatment may actually decrease CNS dopamine turnover in the striatum. 2. A number of epidemiological investigations have demonstrated that individuals who are or who have been smokers are less likely to develop idiopathic Parkinson's disease (a disorder involving a deficit in nigrostriatal dopaminergic neurotransmission). In addition, there is preliminary evidence that individuals with tardive dyskinesia (a hyperkinetic movement disorder observed in some cases of chronic neuroleptic treatment and thought by some to be associated with striatal dopamine receptor supersensitivity) are more likely to be smokers. 3. A unitary hypothesis is presented, proposing that smoking in early adult life may decrease CNS catecholamine turnover, thereby protecting against free radical formation from catecholamine oxidation that in turn damages striatal neurons. These individuals are thereby "protected" from the later development of Parkinson's disease. In this hypothetical scheme, individuals who are given neuroleptics and who also are smokers may develop a greater degree of dopamine receptor supersensitivity due to combined receptor blockade by neuroleptics and a decrease in CNS dopamine turnover caused by nicotine, resulting in an increased prevalence of tardive dyskinesia in this group.
Cell Mol Neurobiol 1988 Sep
PMID:Hypothesis: a nicotine-dopamine interaction linking smoking with Parkinson's disease and tardive dyskinesia. 306 87

We have tested the hypothesis that chronic exposure to the principal constituents of the aqueous fraction of coal tar extracts can lead to the in vivo formation of substances which may produce neurological damage as the result of free radical generation and lipid peroxidation, these may be involved in the etiology of some neurological disorders. Artificial mixtures of the aqueous fraction of coal tar extracts were given in low concentrations to pigmented mice in their drinking water over a 3-month period. This resulted in significant increases in lipid peroxidation in the striatum, cerebellum and liver of the mice under test, the rank order being striatum greater than cerebellum greater than liver. These results are compatible with the possibility that coal tar emissions (as would be recovered or liberated in the burning, refining or beneficiation of coal) constitute a potential source of neurotoxicants with a predilection for damaging the nigrostriatal neuronal pathway. Our observations may thus have identified an important and hitherto unsuspected environmental source of neurotoxic chemicals, a possibility consistent with the proposed involvement of an environmental chemical factor in Parkinson's disease and perhaps in other neurological disorders.
Mol Cell Biochem 1988 Dec
PMID:Pyridine and other coal tar constituents as free radical-generating environmental neurotoxicants. 323 Dec 23

We used the PCR amplification technique in an attempt to characterize further the dopamine D2L receptor expressed in the prolactin-secreting pituitary MMQ cell clone, derived from the prolactin- and ACTH-secreting Buffalo rat 7315 alpha pituitary tumour. By semiquantitative PCR amplification we were unable to detect the mRNA encoding the D2S receptor isoform, which derives from the well-known process of alternative splicing, producing two D2 receptor subtypes (D2L and D2S) in such tissues as the anterior pituitary and the corpus striatum. Although the pharmacology of the D2 receptor has been established in many studies on both native receptors and transfected receptor isoforms, because of the lack of tissues naturally expressing only one receptor isoform, MMQ cells represent the first example of cells uniquely or prevalently expressing only the D2L receptor, conceivably coupled to its native transduction mechanisms. These considerations prompted us to evaluate the pharmacology and the second messenger systems known to be modulated by dopamine. Scatchard analysis of [3H]spiperone binding resulted in a linear plot, consistent with the existence of a single class of binding sites, with a Kd of 0.055 +/- 0.002 nM and a Bmax of 27 +/- 3.5 fmol/mg protein. Competition experiments confirmed the GTP-dependence and the order of potency for agonist and antagonist ligands consistent with binding to a D2 receptor. The inhibitory effects of dopamine on adenylyl cyclase activity, inositol phosphate production and intracellular free calcium concentrations, the latter presumably via the opening of K+ channels, and prolactin secretion, as well as the reversal of the effect by the D2-selective antagonist (-)sulpiride and pretreatment with pertussis toxin, are consistent with the known biological actions of dopamine at D2 receptors. Based on our observations, the MMQ cell line can be considered a useful tool for investigating ligand-receptor interactions to develop new selective dopaminergic D2L ligands for the therapy of dopamine-related disorders such as schizophrenia, depression, Parkinson's disease and drug addiction.
J Mol Endocrinol 1995 Jun
PMID:Absence of D2S dopamine receptor in the prolactin-secreting MMQ pituitary clone: characterization of a wild D2L receptor coupled to native transduction mechanisms. 766 27

Apolipoprotein E (apo E) exists in three allelic, functionally distinct isoforms (apo E2, E3 and E4). Recent work has suggested that apo-E-dependent uptake of lipoproteins may play important roles in the development and maintenance of the nervous system and in the responses to both peripheral and central nervous system injury. If apo-E-mediated transport of lipids were a rate-limiting step in these processes, one might expect that the functional differences between the alleles would be associated with varying predispositions to neurodegenerative and demyelinating diseases. Thus, we looked for an association between particular apo E genotypes and susceptibility to multiple sclerosis and Parkinson's disease. If apo-E-mediated cholesterol uptake were limiting in neuronal growth, one might also expect that apo E2 alleles would slow CNS tumour growth. Accordingly, apo E genotypes were investigated in individuals with sporadic vestibular schwannomas and neurofibromatosis type 2 (NF-2). No significant alteration in the apo E allele distributions was observed in any of these conditions, nor did the apo E genotypes correlate with disease severity. However, we confirmed the previous findings of an over-representation of the apo E4 allele in autopsy-diagnosed late-onset Alzheimer's disease patients. In addition, our data supported the recent observations that apo E2 may be associated with a protective effect for late-onset Alzheimer's disease. These contrasting risks associated with the apo E2 and E4 alleles strengthen the suggestions that this gene is directly involved in the pathogenesis of Alzheimer's disease.
Mol Cell Probes 1994 Dec
PMID:Apo E genotypes in multiple sclerosis, Parkinson's disease, schwannomas and late-onset Alzheimer's disease. 770 Feb 74

Oxidative stress and subsequent energy crisis have been proposed as the cause of nigral neuronal cell death in Parkinson's disease. We have reported defects in the mitochondrial respiratory chain and increased amount of deleted mitochondrial genome in the nigrostriatal system of patients with Parkinson's disease. Deletion in mitochondrial DNA could be ascribed to somatically acquired premature aging leading to cell death. To elucidate the contribution of maternally transmitted point mutations in mitochondrial DNA to the premature DNA damages, we employed a direct sequencing system and analyzed the total nucleotide sequences of mitochondrial DNA in the brains of five patients with idiopathic Parkinson's disease. There were no predominant point mutations among the patients in contrast to some neuromuscular diseases. However, each patient had several point mutations that would result in a significant change in the gene products. Some of these mutations may be involved either in the increased production of oxygen radicals from the mitochondrial respiratory chain or in the increased susceptibility of the respiratory chain components to oxidative damage. We propose that some of these mutations can be regarded as one of the risk factors accelerating degeneration of nigrostriatal pathway in Parkinson's disease.
Brain Res Mol Brain Res 1995 Feb
PMID:Point mutations of mitochondrial genome in Parkinson's disease. 772 27


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