Cellular clones and transgenic mice overexpressing copper — zinc superoxide dismutase: Models for the study of free radical metabolism and aging
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 H2O2overproduction 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.
KeywordsTransgenic Mouse Down Syndrome Glutathione Peroxidase Activity Gene Dosage Effect CuZnSOD Activity
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- Anneren, G., Edqvist, L. E., Gebre-Medhin, M., and Gustavson, K. H. (1985) Glutathione peroxidase activity in erythrocytes in Down’s syndrome. Abnormal variation in relation to age and sex through childhood and adolescence. Trisomy 21. 1: 9–17.Google Scholar
- Auh, B., Caviedes, P., Hidalgo, J., Epstein, C. J., and Rapoport, S. L (1989) Electrophysiological analysis of cultured fetal mouse dorsal root ganglion neurons transgenic for human superoxide dismutase-gene in the Down syndrome region of chromosome 21. Brain Res. 497:191 -194.Google Scholar
- Ceballos, L, Delabar, J. M., Nicole, A., Lynch, R. E., Hallewel, R. A., Kamoun, P., and Sinet, P. M. (1988) Expression of transfected human CuZn superoxide dismutase gene in mouse L cells and NS20Y neuroblastoma cells induces enhancement of glutathione peroxidase activity. Biochim. Biophys. Acta 949: 58–64.PubMedGoogle Scholar
- Ceballos, L, Lafon, M., Javoy-Agid, F., Hirsch, E., Nicole, A., Sinet, P. M., and Agid, Y. (1990a) Superoxide dismutase and Parkinson’s disease. The Lancet, 335: 1035–1036.Google Scholar
- Ceballos, L, Javoy-Agid, F., Delacourte, A., Defossez, A., Nicole, A., and Sinet, P. M. (1990b) Parkinson’s disease and Alzheimer’s disease: neurodegenerative disorders due to brain antioxidant system deficiency? In: Antioxidants in Therapy and Preventive Medicine, Emerit et al. (Eds), Plenum Press, N.Y., p. 493–498.CrossRefGoogle Scholar
- Ceballos, L, Javoy-Agid, F., Delacourte, A., Defossez, A., Lafon, M., Hirsch, E., Nicole, A., Sinet, P. M., and Agid, Y. (1991a) Neuronal localization of copper-zinc superoxide dismutase protein ans mRNA within the human hippocampus from control and Alzheimer’s disease brains. Free Rad. Res. Comms. 12–13: 571–580.CrossRefGoogle Scholar
- Ceballos-Picot, L, Nicole, A., Briand, P., Grimber, G., Delacourte, A., Defossez, A., Javoy-Agid, F., Lafon, M., Blouin, J. L., and Sinet, P. M. (1991b) Neuronal-specific expression of human copper-zinc superoxide dismutase gene in transgenic mice: animal model of gene dosage effect in Down’s syndrome. Brain Res. 552: 198–214.PubMedCrossRefGoogle Scholar
- Ceballos, L, Nicole, A., Briand, P., Grimber, G., Delacourte, A., Flament, S., Thevenin, J. M., Kamoun, P., and Sinet, P. M. (1991c) Expression of human CuZn superoxide dismutase gene in transgenic mice: model for gene dosage effect in Down’s syndrome. Free Rad. Res. Comms. 12–13: 581–589.CrossRefGoogle Scholar
- Chan, P. H., Chu, L., Chen, S., Carlson, E. J., and Epstein, C. J. (1990) Reduced neurotoxicity in transgenic mice overexpressing copper-zinc superoxide dismutase. Stroke Suppl. Ill, 21: 80–82.Google Scholar
- Epstein, C. J., Avraham, K. B., Lovett, M., Smith, S., Elroy-Stein, O., Rotman, G., Bry, C., and Groner, Y. (1987) Transgenic mice with increased Cu/Zn-superoxide dismutase activity: Animal model of gene dosage effects in Down syndrome. Proc. Natl Acad. Sci. 84: 8044–8048.PubMedCrossRefGoogle Scholar
- Kinouchi, H., Mizui, T., Carlson, E., and Epstein, C. J. (1991) Focal cerebral ischemia and the antioxidant system in transgenic mice overexpressing CuZn-superoxide dismutase. J. Cereb. Blood Flow Metab. 11: S423.Google Scholar
- Minc-Colomb, D., Knobler, H., and Groner, Y. (1991) Gene dosage of CuZnSOD and Down’s syndrome: diminished prostaglandin synthesis in human trisomy 21, transfected cells and transgenic mice. EMBO 10: 2119–2124.Google Scholar
- Norris, K. H., and Hornsby, P. J. (1990) Cytotoxic effects of expression of human superoxide dismutase in bovine adrenocortical cells. Mut. Res. 237: 95–106.Google Scholar
- Schickler, M., Knobler, H., Avraham, K. B., Elroy-Stein, O., and Groner, Y. (1989) Diminished serotonin uptake in platelets of transgenic mice with increased Cu/Zn-superoxide dismutase activity. EMBO 8: 1385–1392.Google Scholar
- Schwaiger, H., Weirich, H. G., Brunner, P., Rass, C., Hirsch-Kauffman, M., Groner, Y., and Schweiger, M. (1989) Radiation sensitivity of Down’s syndrome fibroblasts might be due to overexpressed C/Zn-superoxide dismutase (EC 1.15.11). Eur. J. Cell Biol. 48: 79–87.Google Scholar
- Sinet, P. M., Couturier, J., Dutrillaux, A., and Jerome, H. (1976). Trisomie 21 et superoxide dismutase-1 (IPO-A). Tentative de localisation sur la sous-bande 21q22.1. Exp. Cell Res. 97: 47–55.Google Scholar
- Sinet, P. M. (1982) Metabolism of oxygen derivatives in Down’s syndrome. Ann. N.Y. Acad. Sci. 386: 82–94.Google Scholar
- White, C. W., Avraham, K. B., Shanley, P. P., and Groner, Y. (1991) Transgenic mice with expression of elevated levels of copper-zinc superoxide dismutase in the lungs are resistant to pulmonary oxygen toxicity. J. Chn. Invest. 2162–2168.Google Scholar