Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013080 (Down syndrome)
 14,180 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Down's Syndrome (DS), the most frequent of congenital birth defects, results from the trisomy of the chromosome numbered 21 in all cells of affected patients. This disease is characterized by developmental anomalies, mental retardation and features of rapid aging, particularly in the brain where the occurrence of Alzheimer's disease (AD) is observed in all trisomy 21 patients over the age of 35. Elucidation of the biological mechanisms leading to brain aging in DS might provide new insight into the understanding of brain aging and AD in normal people. Copper-zinc superoxide dismutase (CuZnSOD) is one of the genes encoded by chromosome 21. As a consequence of gene dosage excess, CuZnSOD activity and protein are increased by 50% in all DS tissues. The level of CuZnSOD protein and mRNA is particularly high in hippocampal pyramidal neurons susceptible to degenerative processes in AD and in dopaminergic melanized-neurons vulnerable in Parkinson's disease. Increased CuZnSOD activity in these age-related neurodegenerative disorders might result in H2O2 overproduction and subsequently promote peroxidative damages within cells. Increase of seleno-dependent glutathione peroxidase (Se-GPx) in DS cells supports this concept. In order to test this hypothesis, cell and animal models of CuZnSOD overexpression have been designed. In cells transfected with the human CuZnSOD gene, and increased Se-GPx activity is observed, a situation which mimics DS. In mice transgenic for the human CuZnSOD, the expression pattern of the transgene in the brain is similar to that in humans, and we can observe an increased peroxidation in this tissue. These data, like others in the literature, support the hypothesis that excess CuZnSOD induces an imbalance in the regulation of oxygen-derived free radical production which might result in peroxidative brain damage and possibly contribute to accelerated aging and age-related neuropathology.
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PMID:Cellular clones and transgenic mice overexpressing copper-zinc superoxide dismutase: models for the study of free radical metabolism and aging. 145 Jun 8

To protect against reactive oxygen species, prokaryotic and eukaryotic cells have developed an antioxidant defence mechanism where O2- is converted to H2O2 by superoxide dismutase (Sod), and in a second step, H2O2 is converted to H2O by catalase (Cat) and/or glutathione peroxidase (Gpx). If Sod levels are increased without a concomitant Gpx increase, then the intermediate H2O2 accumulates. This intermediate could undergo the Fenton's reaction, generating hydroxyl radicals which may lead to lipid peroxidation in cells. In this study, we investigate the expression of Sod1, Gpx1 and susceptibility to lipid peroxidation during the aging process in mouse brains. We demonstrate that the mRNA levels and enzyme activity of Sod1 are higher in brains from adult mice compared to neonatal mice. Furthermore, we show that a linear increase in Sod1 mRNA and enzyme activity occurs with aging (1-100 weeks). On the contrary, we find that the mRNA and enzyme activity for Gpx1 does not increase with aging in mouse brains. In addition, our results demonstrate that the susceptibility of murine brains to lipid peroxidation increases with aging. The data in this study are consistent with the notion that reactive oxygen species may contribute to the aging process in mammalian brains. These results are discussed in relation to the normal aging process in mammals, and to the premature aging and mental retardation in Down syndrome.
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PMID:Cu/Zn superoxide dismutase mRNA and enzyme activity, and susceptibility to lipid peroxidation, increases with aging in murine brains. 159 44

Previous studies have suggested that free radicals and related species play a role in lens damage. The molecules involved may include proteins, lipids and DNA. Focal cortical changes and cortical liquefaction have been reported in patients with Down's syndrome over the age of 15 years. There is evidence supporting the hypothesis that trisomy 21 patients have an increase in free radical reactions and lipoperoxidation susceptibility. This could be due to an increase in the H2O2 generation catalysed by CuZn SOD although the activity of other gene products coded for on chromosome 21 cannot be excluded. Thiobarbituric acid reactive products were measured in human erythrocytes of nine DS patients and nine age-matched controls. There was a significant increase in the first group (21.0 +/- 2.3 nmol MDA/g Hb vs 16.4 +/- 2.9 nmol MDA/g Hb; p less than or equal to 0.01). In plasma, however, TBA products and antioxidant levels (ascorbic acid, tocopherol and uric acid) were not significantly different. Further studies should be carried out, namely through the use of more specific and sensitive methods, to assess the possible association between oxidative stress and cortical lens damage in DS patients.
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PMID:Oxidative stress in trisomy 21. A possible role in cataractogenesis. 253 64

We examined the tongue muscles in several strains of transgenic mice carrying the human Zn-Cu superoxide dismutase (CuZnSOD) gene. The presence of the extra gene was confirmed in mated progeny and the gene product activity was measured in the tongue and found to be much higher than in normal littermate controls. Using electron microscopic morphometry, the neuromuscular junctions of the transgenic mice showed significant changes resembling excessive aging, with atrophy, degeneration, withdrawal, and sometimes destruction of the terminal axons, as well as the development of multiple small terminals. The myofibers showed little change except for slight hypertrophy and an increased variability in size. They also had more megamitochondria, fat droplets and lipofuscin bodies. Excess CuZnSOD generates H2O2 and hydroxyl radicals which affect both NMJ membranes and plasticity, and which may produce premature aging. The findings resemble those observed in tongues of patients with Down's syndrome, in whom an extra CuZnSOD gene is present as part of the trisomy of chromosome 21.
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PMID:Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome. 297 83

Enzymes of importance for oxygen dependent leukocyte killing of microorganisms were studied in 14 patients with Down's Syndrome (DS) and 10 controls. As has been reported previously for other cell types, the level of CuZn superoxide dismutase (SOD) was 50% higher in polymorphonuclear leukocytes (PMN) from DS patients than from the controls. The amount of SOD was extremely low in the PMNs from controls, i.e. only about 6% of the levels in other human tissues. The levels of catalase and of the Mn dependent SOD were normal. The myeloperoxidase (MPO) activity of DS PMNs was only 59% of that of the control cells. Previously reported increased levels of CuZnSOD and GSH peroxidase in erythrocytes and CuZnSOD in lymphocytes were confirmed. The increased levels of SOD in DS phagocytes provide a possible partial explanation for previous reports of defective killing of S. aureus in DS. In addition, the MPO deficiency impairs the H2O2-halide-MPO system, which is of particular importance for fungal killing, e.g. of C. albicans, which has also been reported to be deficient in DS. The findings may thus explain some of the mechanisms underlying the increased susceptibility to certain infections in DS.
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PMID:Enzymes of leukocyte oxidative metabolism in Down's syndrome. 632 10

During oxidative metabolism harmful reactive oxygen species (ROS) are generated. These species are neutralized by antioxidant enzymes. Firstly, superoxide dismutase (Sod) converts superoxide radicals (.O2-) to hydrogen peroxide (H2O2). Thereafter catalase (Cat) and glutathione peroxidase (Gpx) independently convert this to water. An imbalance in the ratio of Sod to Gpx and Cat results in the accumulation of H2O2 which may participate in the Fenton reaction, resulting in the formation of noxious hydroxyl radicals. These ROS are highly reactive and cause damage to macromolecules such as DNA, protein and lipids. We propose that it is the balance in the activity of the Sod to Gpx plus Cat ratio (Sod/(Gpx plus Cat)) that is an important determinant of cellular aging. This is based on our observation that an altered Cu/Zn-superoxide dismutase (Sod1)/(Gpx1 plus Cat) ratio exists in the brain of aging mice and that this correlates with increased lipid damage. Conversely, aging liver and kidney have an unaffected Sod1/(Gpx1 plus Cat) ratio and lipid damage is not increased with aging. We also examine the Sod1 to Gpx1 ratio in Down syndrome tissue and show that all organs have an altered ratio. This may contribute to the premature aging seen in these individuals. We show that binding of a p50/p65 complex to an NF-kappa B consensus sequence is enhanced by H2O2 treatment in NIH3T3 cells. Thus an altered Sod1/(Gpx1 plus Cat) ratio may also affect gene expression by altering the binding and/or availability of transcription factors to DNA.
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PMID:Cu/Zn-superoxide dismutase and glutathione peroxidase during aging. 749 66

In response to certain stimuli, polymorphonuclear leukocytes (PMNs) undergo an oxidative burst during which a series of reactive oxygen metabolites are generated. The importance of the release of these oxygen metabolites by polymorphonuclear leukocytes, is recognized to be a key event in the function of these cells during infection and inflammation. We have evaluated the release of reactive oxygen species during the activation of respiratory burst (RB) of PMNs obtained from children with trisomy 21 using chemiluminescence techniques. As chemiluminogenic probes we have employed lucigenin and luminon that are know to be sensitive to the superoxide anion and the H2O2-myeloperoxidase-halide system of PMNs, respectively. Activated PMNs from children with trisomy 21 exhibited a low level of superoxide and a reduced activity of H2O2-myeloperoxidase-halide system compared to the control group. No significant difference in extracellular H2O2 release was observed. It seems likely that alterations in the enzymatic activities of the Cu/Zn-Superoxide dismutase and myeloperoxidase induce imbalance in the release of reactive oxygen species in activated PMNs from children with trisomy 21. This imbalance could be on the basis of the increased oxidative injury reported in trisomy 21.
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PMID:[Oxidative metabolism in polymorphonuclear granulocytes of children with trisomy 21]. 814 84

Although reactive oxygen species have been proposed to play a major role in the aging process, the exact molecular mechanisms remain elusive. In this study we investigate the effects of a perturbation in the ratio of Cu/Zn-superoxide dismutase activity (Sod1 dismutases .O2-to H2O2) to glutathione peroxidase activity (Gpx1 catalyses H2O2 conversion to H2O) on cell growth and development. Our data demonstrate that Sod1 transfected cell lines that have an elevation in the ratio of Sod1 activity to Gpx1 activity produce higher levels of H2O2 and exhibit well characterised markers of cellular senescence viz. slower proliferation and altered morphology. On the contrary, Sod1 transfected cell lines that have an unaltered ratio in the activity of these two enzymes, have unaltered levels of H2O2 and fail to show characteristics of senescence. Furthermore, fibroblasts established from individuals with Down syndrome have an increase in the ratio of Sod1 to Gpx1 activity compared with corresponding controls and senesce earlier. Interestingly, cells treated with H2O2 also show features of senescence and/or senesce earlier. We also show that Cip1 mRNA levels are elevated in Down syndrome cells, Sod1 transfectants with an altered Sod1 to Gpx1 activity ratio and those treated with H2O2, thus suggesting that the slow proliferation may be mediated by Cip1. Furthermore, our data demonstrate that Cip1 mRNA levels are induced by exposure of cells to H2O2. These data give valuable insight into possible molecular mechanisms that contribute tribute to cellular senescence and may be useful in the evolution of therapeutic strategies for aging.
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PMID:Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. 882 85

We are using the technique of mRNA differential display to identify RNAs that may be important in protecting cells against the damaging effects of oxidative stress. For these studies, we utilize a so-called "adaptive response" model system in which hamster HA-1 cells respond to a minimally toxic "pretreatment" dose of hydrogen peroxide by synthesizing RNAs and proteins that protect them against subsequent exposure to a highly cytotoxic concentration of hydrogen peroxide. Using this approach, we have recently reported several novel RNAs whose levels are increased under conditions of adaptive response. Here we report a new RNA, designated adapt78, whose steady-state level is significantly induced by a pretreatment dose of hydrogen peroxide. adapt78 mRNA was calculated to be 2.35 kb in size and inducible by the standard pretreatment dose of 4 micromol H2O2/10(7) cells. It was induced as early as 90 min after peroxide exposure and maximally at 5 h. Induction was strongly dependent upon calcium. Cloning and sequencing revealed a large predicted open reading frame of 197 amino acids. In vitro transcription and translation generated a protein of 25,000 Da. GenBank homology analysis revealed that much of adapt78 is strongly homologous to a sequence that has been mapped to the Down syndrome critical region (Fuentes et al., Hum. Mol. Genet. 4, 1935-1944, 1995). However, both the 5' and the 3' ends of adapt78 show no homology to any previously reported complete sequence. adapt78 represents a new oxidant-inducible RNA and marker of cellular oxidative stress and may provide new insight into our understanding of oxidant-related disorders and neural degeneration.
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PMID:Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. 918 8

The human Cu/Zn superoxide dismutase (hSOD-1) gene, catalyses the dismutation of O2 to H2O2 and O2. It is located on chromosome 21 in q22.1 and is overexpressed in Down's syndrome (DS) patients. These patients present various abnormalities including mental retardation, congenital heart disease, immunological deficits and premature aging. In order to explore the potential role of SOD-1 overexpression in DS, we have generated two lineages of transgenic mice for the hSOD-1 gene and studied, at the ultrastructural level, the effect of hSOD-1 overexpression on the thymic microenvironment. Modification of the cellular architecture and morphology associated with a lipidic invasion, signs of a premature involution of the thymus, were observed in both lineages. A rupture of the filamentous network in the extracellular and probably also in the intracellular matrix was first observed. These results correlate the thymic alterations visualized in light microscopy, on the thymus from DS patients, and raise the question of the relationship between the SOD-1 overexpression and the different morphological alterations associated with the premature thymic involution observed in SOD-1 transgenic mice. They suggest that thymic and immunological impairments present in DS patients may be related to the SOD-1 gene dosage effect.
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PMID:Premature thymic involution, observed at the ultrastructural level, in two lineages of human-SOD-1 transgenic mice. 922 11


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