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. 1989 May;8(5):1385–1392. doi: 10.1002/j.1460-2075.1989.tb03519.x

Diminished serotonin uptake in platelets of transgenic mice with increased Cu/Zn-superoxide dismutase activity.

M Schickler 1, H Knobler 1, K B Avraham 1, O Elroy-Stein 1, Y Groner 1
PMCID: PMC400965  PMID: 2527742

Abstract

Reduced levels of the neurotransmitter serotonin in blood platelets is a clinical symptom characteristic of individuals with Down's syndrome. To investigate the possible involvement of the Cu/Zn-superoxide dismutase (CuZnSOD) gene, which resides at the Down locus on chromosome no. 21, in the etiology of that symptom, we examined blood platelets of transgenic mice harboring the human CuZnSOD gene. It was found that platelets of transgenic CuZnSOD animals, which overexpress the transgene, contain lower levels of serotonin than nontransgenic littermate mice, due to a reduced rate of uptake of the neurotransmitter by the dense granules of the platelets. We found that the pH gradient (delta pH) across the dense granule membrane, which is the main driving force for serotonin transport, was diminished in dense granules of transgenic-CuZnSOD. Furthermore, a significantly lower than normal serotonin accumulation rate was also detected in dense granules isolated from blood platelets of Down's syndrome individuals. These findings suggest that CuZnSOD gene dosage is affecting the dense granule transport system and is thereby involved in the depressed level of blood serotonin found in patients born with Down's syndrome.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avraham K. B., Schickler M., Sapoznikov D., Yarom R., Groner Y. Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase. Cell. 1988 Sep 9;54(6):823–829. doi: 10.1016/s0092-8674(88)91153-1. [DOI] [PubMed] [Google Scholar]
  2. Badwey J. A., Karnovsky M. L. Active oxygen species and the functions of phagocytic leukocytes. Annu Rev Biochem. 1980;49:695–726. doi: 10.1146/annurev.bi.49.070180.003403. [DOI] [PubMed] [Google Scholar]
  3. Balazs R., Brooksbank B. W. Neurochemical approaches to the pathogenesis of Down's syndrome. J Ment Defic Res. 1985 Mar;29(Pt 1):1–14. doi: 10.1111/j.1365-2788.1985.tb00302.x. [DOI] [PubMed] [Google Scholar]
  4. Barber A. J., Jamieson G. A. Isolation and characterization of plasma membranes from human blood platelets. J Biol Chem. 1970 Dec 10;245(23):6357–6365. [PubMed] [Google Scholar]
  5. Bazelon M., Barnet A., Lodge A., Shelburne S. A., Jr The effect of high doses of 5-hydroxytryptophan on a patient with trisomy 21. Clinical, chemical and EEG correlations. Brain Res. 1968 Nov;11(2):397–411. doi: 10.1016/0006-8993(68)90033-4. [DOI] [PubMed] [Google Scholar]
  6. Bazelon M., Paine R. S., Coeiw V. A., Hunt P., Houck J. C., Mahanand D. Reversal of hypotonia in infants with Down's syndrome by administration of 5-hydroxytryptophan. Lancet. 1967 May 27;1(7500):1130–1133. doi: 10.1016/s0140-6736(67)91708-4. [DOI] [PubMed] [Google Scholar]
  7. Bernard O., Cory S., Gerondakis S., Webb E., Adams J. M. Sequence of the murine and human cellular myc oncogenes and two modes of myc transcription resulting from chromosome translocation in B lymphoid tumours. EMBO J. 1983;2(12):2375–2383. doi: 10.1002/j.1460-2075.1983.tb01749.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cerutti P. A. Prooxidant states and tumor promotion. Science. 1985 Jan 25;227(4685):375–381. doi: 10.1126/science.2981433. [DOI] [PubMed] [Google Scholar]
  9. Coleman M. Infantile spasms associated with 5-hydroxytryptophan administration in patients with Down's syndrome. Neurology. 1971 Sep;21(9):911–919. doi: 10.1212/wnl.21.9.911. [DOI] [PubMed] [Google Scholar]
  10. Cools A. A., Janssen L. H. Fluorescence response of acridine orange to changes in pH gradients across liposome membranes. Experientia. 1986 Aug 15;42(8):954–956. doi: 10.1007/BF01941777. [DOI] [PubMed] [Google Scholar]
  11. Cooper D. N., Hall C. Down's syndrome and the molecular biology of chromosome 21. Prog Neurobiol. 1988;30(6):507–530. doi: 10.1016/0301-0082(88)90033-0. [DOI] [PubMed] [Google Scholar]
  12. Coyle J. T., Oster-Granite M. L., Gearhart J. D. The neurobiologic consequences of Down syndrome. Brain Res Bull. 1986 Jun;16(6):773–787. doi: 10.1016/0361-9230(86)90074-2. [DOI] [PubMed] [Google Scholar]
  13. Elroy-Stein O., Bernstein Y., Groner Y. Overproduction of human Cu/Zn-superoxide dismutase in transfected cells: extenuation of paraquat-mediated cytotoxicity and enhancement of lipid peroxidation. EMBO J. 1986 Mar;5(3):615–622. doi: 10.1002/j.1460-2075.1986.tb04255.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Elroy-Stein O., Groner Y. Impaired neurotransmitter uptake in PC12 cells overexpressing human Cu/Zn-superoxide dismutase--implication for gene dosage effects in Down syndrome. Cell. 1988 Jan 29;52(2):259–267. doi: 10.1016/0092-8674(88)90515-6. [DOI] [PubMed] [Google Scholar]
  15. Epstein C. J., Avraham K. B., Lovett M., Smith S., Elroy-Stein O., Rotman G., Bry C., Groner Y. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8044–8048. doi: 10.1073/pnas.84.22.8044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Finazzi-Agró A., Di Giulio A., Amicosante G., Crifó C. Photohemolysis of erythrocytes enriched with superoxide dismutase, catalase and glutathione peroxidase. Photochem Photobiol. 1986 Apr;43(4):409–412. doi: 10.1111/j.1751-1097.1986.tb05622.x. [DOI] [PubMed] [Google Scholar]
  17. Fishkes H., Rudnick G. Bioenergetics of serotonin transport by membrane vesicles derived from platelet dense granules. J Biol Chem. 1982 May 25;257(10):5671–5677. [PubMed] [Google Scholar]
  18. Gasko O. D., Knowles A. F., Shertzer H. G., Suolinna E. M., Racker E. The use of ion-exchange resins for studying ion transport in biological systems. Anal Biochem. 1976 May 7;72:57–65. doi: 10.1016/0003-2697(76)90506-6. [DOI] [PubMed] [Google Scholar]
  19. Grahame-Smith D. G. Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J Neurochem. 1971 Jun;18(6):1053–1066. doi: 10.1111/j.1471-4159.1971.tb12034.x. [DOI] [PubMed] [Google Scholar]
  20. Groner Y., Elroy-Stein O., Bernstein Y., Dafni N., Levanon D., Danciger E., Neer A. Molecular genetics of Down's syndrome: overexpression of transfected human Cu/Zn-superoxide dismutase gene and the consequent physiological changes. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):381–393. doi: 10.1101/sqb.1986.051.01.046. [DOI] [PubMed] [Google Scholar]
  21. Groner Y., Lieman-Hurwitz J., Dafni N., Sherman L., Levanon D., Bernstein Y., Danciger E., Elroy-Stein O. Molecular structure and expression of the gene locus on chromosome 21 encoding the Cu/Zn superoxide dismutase and its relevance to Down syndrome. Ann N Y Acad Sci. 1985;450:133–156. doi: 10.1111/j.1749-6632.1985.tb21489.x. [DOI] [PubMed] [Google Scholar]
  22. Hebbel R. P., Shalev O., Foker W., Rank B. H. Inhibition of erythrocyte Ca2+-ATPase by activated oxygen through thiol- and lipid-dependent mechanisms. Biochim Biophys Acta. 1986 Nov 6;862(1):8–16. doi: 10.1016/0005-2736(86)90463-3. [DOI] [PubMed] [Google Scholar]
  23. Iwahashi H., Ishii T., Sugata R., Kido R. Superoxide dismutase enhances the formation of hydroxyl radicals in the reaction of 3-hydroxyanthranilic acid with molecular oxygen. Biochem J. 1988 May 1;251(3):893–899. doi: 10.1042/bj2510893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jacobs B. L. An animal behavior model for studying central serotonergic synapses. Life Sci. 1976 Sep 15;19(6):777–785. doi: 10.1016/0024-3205(76)90303-9. [DOI] [PubMed] [Google Scholar]
  25. Jacobs B. L., Klemfuss H. Brain stem and spinal cord mediation of a serotonergic behavioral syndrome. Brain Res. 1975 Dec 19;100(2):450–457. doi: 10.1016/0006-8993(75)90500-4. [DOI] [PubMed] [Google Scholar]
  26. Kanner B. I., Fishkes H., Maron R., Sharon I., Schuldiner S. Reserpine as a competitive and reversible inhibitor of the catecholamine transporter of bovine chromaffin granules. FEBS Lett. 1979 Apr 1;100(1):175–178. doi: 10.1016/0014-5793(79)81158-8. [DOI] [PubMed] [Google Scholar]
  27. LEJEUNE J., GAUTIER M., TURPIN R. Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci. 1959 Mar 16;248(11):1721–1722. [PubMed] [Google Scholar]
  28. Lauder J. M., Krebs H. Serotonin as a differentiation signal in early neurogenesis. Dev Neurosci. 1978;1(1):15–30. doi: 10.1159/000112549. [DOI] [PubMed] [Google Scholar]
  29. Levanon D., Lieman-Hurwitz J., Dafni N., Wigderson M., Sherman L., Bernstein Y., Laver-Rudich Z., Danciger E., Stein O., Groner Y. Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J. 1985 Jan;4(1):77–84. doi: 10.1002/j.1460-2075.1985.tb02320.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. MARSHALL E. F., STIRLING G. S., TAIT A. C., TODRICK A. The effect of iproniazid and imipramine on the blood platelet 5-hydroxytrptamine level in man. Br J Pharmacol Chemother. 1960 Mar;15:35–41. doi: 10.1111/j.1476-5381.1960.tb01207.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Massari S., Pascolini D., Gradenigo G. Distribution of negative phospholipids in mixed vesicles. Biochemistry. 1978 Oct 17;17(21):4465–4469. doi: 10.1021/bi00614a016. [DOI] [PubMed] [Google Scholar]
  32. McCoy E. E., Enns L. Sodium transport ouabain binding, and (Na+/K+)-ATPase activity in Down's syndrome platelets. Pediatr Res. 1978 Jun;12(6):685–689. doi: 10.1203/00006450-197806000-00001. [DOI] [PubMed] [Google Scholar]
  33. Palmiter R. D., Brinster R. L. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465–499. doi: 10.1146/annurev.ge.20.120186.002341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Petre-Quadens O., De Greef A. Effects of 5-HTP on sleep in Mongol children. Preliminary results. J Neurol Sci. 1971 May;13(1):115–119. doi: 10.1016/0022-510x(71)90211-5. [DOI] [PubMed] [Google Scholar]
  35. Porter N. A. Chemistry of lipid peroxidation. Methods Enzymol. 1984;105:273–282. doi: 10.1016/s0076-6879(84)05035-7. [DOI] [PubMed] [Google Scholar]
  36. ROSNER F., ONG B. H., PAINE R. S., MAHANAND D. BLOOD-SEROTONIN ACTIVITY IN TRISOMIC AND TRANSLOCATION DOWN'S SYNDROME. Lancet. 1965 Jun 5;1(7397):1191–1193. doi: 10.1016/s0140-6736(65)92722-4. [DOI] [PubMed] [Google Scholar]
  37. Rao G. H., White J. G., Jachimowicz A. A., Witkop C. J. An improved method for the extraction of endogenous platelet serotonin. J Lab Clin Med. 1976 Jan;87(1):129–137. [PubMed] [Google Scholar]
  38. Rudnick G. ATP-driven H+ pumping into intracellular organelles. Annu Rev Physiol. 1986;48:403–413. doi: 10.1146/annurev.ph.48.030186.002155. [DOI] [PubMed] [Google Scholar]
  39. Rudnick G., Fishkes H., Nelson P. J., Schuldiner S. Evidence for two distinct serotonin transport systems in platelets. J Biol Chem. 1980 Apr 25;255(8):3638–3641. [PubMed] [Google Scholar]
  40. Rudnick G., Nelson P. J. Platelet 5-hydroxytryptamine transport, an electroneutral mechanism coupled to potassium. Biochemistry. 1978 Oct 31;17(22):4739–4742. doi: 10.1021/bi00615a021. [DOI] [PubMed] [Google Scholar]
  41. Scoggin C. H., Patterson D. Down's syndrome as a model disease. Arch Intern Med. 1982 Mar;142(3):462–464. [PubMed] [Google Scholar]
  42. Scott M. D., Meshnick S. R., Eaton J. W. Superoxide dismutase-rich bacteria. Paradoxical increase in oxidant toxicity. J Biol Chem. 1987 Mar 15;262(8):3640–3645. [PubMed] [Google Scholar]
  43. Shahak Y. Activation and Deactivation of H-ATPase in Intact Chloroplasts. Plant Physiol. 1982 Jul;70(1):87–91. doi: 10.1104/pp.70.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sneddon J. M. Blood platelets as a model for monoamine-containing neurones. Prog Neurobiol. 1973;1(2):151–198. doi: 10.1016/0301-0082(73)90019-1. [DOI] [PubMed] [Google Scholar]
  45. Tappel A. L. Lipid peroxidation damage to cell components. Fed Proc. 1973 Aug;32(8):1870–1874. [PubMed] [Google Scholar]
  46. Tu J. B., Zellweger H. Blood-serotonin deficiency in Down's syndrome. Lancet. 1965 Oct 9;2(7415):715–716. doi: 10.1016/s0140-6736(65)90454-x. [DOI] [PubMed] [Google Scholar]
  47. Wilkins J. A., Salganicoff L. Participation of a transmembrane proton gradient in 5-hydroxytryptamine transport by platelet dense granules and dense-granule ghosts. Biochem J. 1981 Jul 15;198(1):113–123. doi: 10.1042/bj1980113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yarom R., Sapoznikov D., Havivi Y., Avraham K. B., Schickler M., Groner Y. Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome. J Neurol Sci. 1988 Dec;88(1-3):41–53. doi: 10.1016/0022-510x(88)90204-3. [DOI] [PubMed] [Google Scholar]

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