Summary
Transgenic mice carrying the human CuZn-superoxide dismutase gene were used to investigate whether CuZn-superoxide dismutase gene dosage is involved in the signs of neuromuscular junction deterioration associated with Down's syndrome. Three parameters of neuromuscular junction morphology were studied in hindlimb muscles of CuZn-superoxide dismutase-transgenic mice and their non-transgenic littermates: nerve terminal length, number of nerve terminal branching points and incidence of sprouting that results in synapse formation. These parameters increased with advanced age and the increase occurred earlier in CuZn-superoxide dismutase-transgenic mice. Therefore, the data is in line with the possibility that CuZn-superoxide dismutase-transgenic mice are undergoing premature ageing with respect to neuromuscular junction morphology, most probably owing to a gene dosage effect of CuZn-superoxide dismutase.
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Andonian, M. H. &Fahim, M. A. (1987) Effects of endurance exercise on the morphology of mouse neuromuscular junctions during aging.Journal of Neurocytology 16, 589–99.
Andonian, M. H. &Fahim, M. A. (1989) Nerve terminal morphology in C57BL/6NNia mice at different ages.Journal of Gerontology 44, B43–51.
Avraham, K. B., Schickler, M., Sapoznikov, D., Yarom, R. &Groner, Y. (1988) Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase.Cell 54, 823–9.
Badwey, J. A. &Karnovsky, L. M. (1980) Active oxygen species and the functions of phagocytic leukocytes.Annual Review of Biochemistry 49, 695–726.
Balazs, R. &Brooksbank, B. W. L. (1985) Neurochemical approaches to the pathogenesis of Down's syndrome.Journal of Mental Deficiency Research 29, 1–14.
Barker, D. &Ip, M. C. (1966) Sprouting and degeneration of mammalian motor axons in normal and de-afferentated skeletal muscle.Proceedings of the Royal Society of London B 163, 538–54.
Cardasis, C. A. (1983) Ultrastructural evidence of continued reorganization at the aging (11–26 months) rat soleus neuromuscular junction.Anatomical Record 207, 399–415.
Cardasis, C. A. &Lafontaine, D. M. (1987) Aging rat neuromuscular junctions: a morphometric study of cholinesterase-stained whole mounts and ultrastructure.Muscle and Nerve 10, 200–13.
Cerutti, P. A. (1985) Pro-oxidant states and tumor production.Science 227, 375–81.
Cooper, D. N. &Hall, C. (1988) Down's syndrome and the molecular biology of chromosome 21.Progress in Neurobiology 30, 507–30.
Elroy-Stein, O. &Groner, Y. (1988) Impaired neurotransmitter uptake in PC12 cells overexpressing human Cu/ Zn-superoxide dismutase — implication for gene dosage effects in Down's syndrome.Cell 52, 259–67.
Elroy-Stein, O., Bernstein, Y. &Groner, Y. (1986) Overproduction of human Cu/Zn-superoxide dismutase in transfected cells: extenuation of paraquat-mediated cytotoxicity and enhancement of lipid peroxidation.EMBO Journal 5, 615–22.
Elstner, E. F. &Heupel, A. (1976) Inhibition of nitrite fomation from hydroxyl ammonium-chloride: a simple assay for Superoxide dismutase.Analytical Biochemistry 70, 616–20.
Epstein, C. J. (1986a)The Consequences of Chromosomal Imbalance. Principles, Mechanisms, Models. New York: Cambridge University Press.
Epstein, C. J. (1986b)The Neurobiology of Down Syndrome. New York: Raven Press.
Epstein, C. J., Avraham, K. B., Lovett, M., Smith, S., Elroy-Stein, O., Rotman, G., Bry, C. &Groner, Y. (1987) Transgenic mice with increased CuZn-superoxide dismutase activity: an animal model of dosage effects in Down's syndrome.Proceedings of the National Academy of Sciences (USA) 84, 8044–8.
Fagg, G. E., Scheff, S. W. &Cotman, C. W. (1981) Axonal sprouting of the neuromuscular junction of adult and aged rats.Experimental Neurology 74, 847–54.
Fahim, M. A., Holley, J. A. &Robbins, N. (1983) Scanning and light microscopic study of age changes at a neuromuscular junction in the mouse.Journal of Neurocytology 12, 13–25.
Fahim, M. A. &Robbins, N. (1982) Ultrastructural studies of young and old mouse neuromuscular junctions.Journal of Neurocytology 11, 641–56.
Fridovich, I. (1986) Superoxide dismutases. InAdvances in Enzymology and Related Areas of Molecular Biology (edited byMeiser, A.), Vol. 58, pp. 61–97. New York: John Wiley.
Groner, Y., Dafni, N., Sherman, L., Levanon, D., Bernstein, Y., Danciger, E., Elroy-Stein, O. &Neer, A. (1986) Down's syndrome and Alzheimer's disease: are common genes from human chromosome 21 involved in both disorders? InAlzheimer's and Parkinson's Disease (edited byFisher, A., Hanin, I. &Lachman, C.) pp. 271–85. New York: Plenum Press.
Groner, Y., Lieman-Hurwitz, J., Dafni, N., Sherman, L., Levanon, D., Bernstein, Y., Danciger, E. &Elroy-Stein, O. (1985) Molecular structure and expression of the gene locus on chromosome 21 encoding the Cu/Zn-superoxide dismutase and its relevance to Down's syndrome.Annals of the New York Academy of Sciences 450, 133–56.
Halliwell, B. &Gutteridge, J. M. C. (1985)Free Radicals in Biology and Medicine. Oxford: Clarendon Press.
Lichtman, J. W., Magrassi, L. &Purves, D. (1987) Visualization of neuromuscular junctions over periods of several months in living mice.Journal of Neuroscience 7, 1215–22.
Pestronk, A., Drachman, D. B. &Griffin, J. W. (1980) Effects of aging on nerve sprouting and regeneration.Experimental Neurology 70, 65–82.
Robbins, N. &Fahim, M. A. (1985) Progression of age changes in mature mouse motor nerve terminals and its relation to locomotor activity.Journal of Neurocytology 14, 1019–36.
Rotshenker, S. (1988) Multiple modes and sites for the induction of axonal growth.Trends in Neurosciences 11, 363–6.
Rotshenker, S. &Tal, M. (1985) The transneuronal induction of sprouting and synapse formation in intact mouse muscles.Journal of Physiology 360, 387–96.
Schickler, M., Knobler, H., Avraham, K. B., Elroystein, O. &Groner, Y. (1989) Diminished serotonin uptake in platelets of transgenic mice with increased Cu/Zn-superoxide dismutase activity.EMBO Journal 8, 1385–92.
Siegel, S. (1956)Nonparametric Statistics for the Behavioral Sciences. New York: McGraw-Hill.
Summitt, R. L. (1981) Chromosome 21: specific segments that cause the phenotype of Down's syndrome. InTrisomy 21 (Down's Syndrome): Research Perspectives (edited byDe La Cruz, F. F. &Gerald, P. S.) pp. 225–35. Baltimore: University Park Press.
Tappel, A. L. (1973) Lipid peroxidation damage to cell components.Federation Proceedings 32, 1870–4.
Tuffery, A. R. (1971) Growth and degeneration of motor end-plates in normal cat hind limb muscles.Journal of Anatomy 110, 221–47.
Wernig, A., Carmody, J. J., Anzil, A. P., Hansert, E., Marciniak, M. &Zucker, H. (1984) Persistence of nerve sprouting with features of synapse remodelling in soleus muscles of adult mice.Neuroscience 11, 241–53.
Wernig, A. &Herrera, A. A. (1986) Sprouting and remodelling at the nerve-muscle junction.Progress in Neurobiology 27, 251–91.
Yarom, R., Sagher, U., Havivi, Y., Peled, I. J. &Wexler, M. R. (1986) Myofibers in tongues of Down's syndrome.Journal of the Neurological Sciences 73, 279–87.
Yarom, R., Sapoznikov, D., Havivi, Y., Avraham, K. B., Schickler, M. &Groner, Y. (1988) Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome.Journal of the Neurological Sciences 88, 41–53.
Yarom, R., Sherman, Y., Sagher, U., Peled, I. J. &Wexler, M. R. (1987) Elevated concentrations of elements and abnormalities of neuromuscular junctions in tongue muscles of Down's syndrome.Journal of the Neurological Sciences 79, 315–26.
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Avraham, K.B., Sugarman, H., Rotshenker, S. et al. Down's syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice. J Neurocytol 20, 208–215 (1991). https://doi.org/10.1007/BF01186993
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DOI: https://doi.org/10.1007/BF01186993