Perspectives on the Mechanisms of Familial Amyotrophic Lateral Sclerosis Caused by Mutations in Superoxide Dismutase 1

  • David R. Borchelt
  • Philip C. Wong
  • Mark W. Becher
  • Lucie I. Bruijn
  • Don W. Cleveland
  • Neal G. Copeland
  • Valeria C. Culotta
  • Nancy A. Jenkins
  • Michael K. Lee
  • Carlos A. Pardo
  • Donald L. Price
  • Sangram S. Sisodia
  • Zhou-Shang Xu


The mechanisms that lead to the selective degeneration of motor neurons in familial and sporadic amyotrophic lateral sclerosis (FALS and ALS) are not clearly understood. A subset of FALS cases are caused by mutations in Cu/Zn superoxide dismutase 1 (SOD1) (Deng et al., 1993; Rosen et al., 1993), but the mechanism by which mutant SOD1 injure motor neurons is unclear. We have suggested that abnormalities in Cu+ + metabolism may play a role in disease (Wong et al., 1995). This speculation derives from a number of observations: Cu++ can catalyze the formation of toxic radical species (Olanow, 1993; Brown, 1995); SOD1 is abundant in nervous tissues (Pardo et al., 1995; Tsuda et al., 1994); and the metal binding domains of the enzyme generally lack mutations (Brown, 1995; Wong and Borchelt, 1995). Moreover, several investigations have demonstrated that FALS-linked mutations do not necessarily compromise free radical scavenging activity (Borchelt et al., 1994; Fujii et al., 1995; Rabizadeh et al., 1995), and transgenic mice expressing mutant SOD1 develop motor neuron disease (MND) despite elevated or unchanged levels of superoxide scavenging activity (Gurney et al., 1994; Ripps et al., 1995; Wong et al., 1995). Although these data suggest that abnormal Cu++ metabolism could play a role in the disease, it is not clear whether mutations in SOD1 alter the levels of free Cu++ by diminishing the functions of an abundant Cu++-binding protein or whether mutations alter SOD1 structure to allow enzyme-bound Cu++ to catalyze deleterious reactions, such as protein nitration (Beck-man et al., 1993) or peroxidation (Stadtman, 1990; Yim et al., 1990; Stadtman and Oliver, 1991; Yim et al., 1993; Wiedau-Pazos et al., 1996).


Superoxide Dismutase Amyotrophic Lateral Sclerosis Motor Neuron Amyotrophic Lateral Sclerosis Patient Motor Neuron Disease 
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  1. Abe, K., Pan, L. H., Watanabe, M., Kato, T., and Itoyama, Y., 1995, Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis, Neurosci. Lett. 199:152–154.PubMedCrossRefGoogle Scholar
  2. Alexianu, M. E., Ho, B.-K., Mohamed, A. H., La Bella, V., Smith, R. G., and Appel, S. H., 1994, The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis, Ann. Neurol. 36:846–858.PubMedCrossRefGoogle Scholar
  3. Aoki, M., Ogasawara, M., Matsubara, Y., Narisawa, K., Nakamura, S., Itoyama, Y, and Abe, K., 1994, Familial amyotrophic lateral sclerosis ALS in Japan associated with H46R mutation in Cu/Zn superoxide dismutase gene: A possible new subtype of familial ALS, J. Neurol. Sci. 126:77–83.PubMedCrossRefGoogle Scholar
  4. Banker, B. Q., 1986, The pathology of motor neuron disorders, in Myology (A. G. Engel and B. Q. Banker, eds.), McGraw Hill, New York, p. 2031.Google Scholar
  5. Beal, M. F., 1995, Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38:357–366.PubMedCrossRefGoogle Scholar
  6. Beal, M. F., Hyman, B. T, and Koroshetz, W., 1995, Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases?, Trends Neurosci. 16:125–131.CrossRefGoogle Scholar
  7. Beckman, J. S., Carson, M., Smith, C. D., and Koppenol, W. H., 1993, ALS, SOD and peroxynitrite, Nature 364:584.PubMedCrossRefGoogle Scholar
  8. Bermingham-McDonogh, O., Gralla, E. B., and Valentine, J. S., 1988, The copper, zinc-superoxide dismutase gene of Saccharomyces cerevisiae: Cloning, sequencing, and biological activity, Proc. Natl. Acad. Sci. USA 85:4789–4793.PubMedCrossRefGoogle Scholar
  9. Bilinski, T., Krawiec, Z., Liczmanski, A., and Litwinska, J., 1985, Is hydroxyl radical generated by the Fenton reaction in vivo?, Biochem. Biophys. Res. Commun. 130:533–539.PubMedCrossRefGoogle Scholar
  10. Borchelt, D. R., Lee, M. K., Slunt, H. H., Guarnieri, M., Xu, Z.-S., Wong, P. C., Brown, R. H., Jr., Price, D. L., Sisodia, S. S., and Cleveland, D. W., 1994, Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity, Proc. Natl. Acad. Sci. USA 91:8292–8296.PubMedCrossRefGoogle Scholar
  11. Borchelt, D. R., Guarnieri, M., Wong, P. C., Lee, M. K., Slunt, H. S., Xu Z., Sisodia, S. S., Price, D. L., and Cleveland, D. W, 1995, Superoxide dismutase 1 subunits with mutations linked to familial amyotrophic lateral sclerosis do not affect wild-type subunit function, J. Biol. Chem. 270:3234–3238.PubMedCrossRefGoogle Scholar
  12. Bowling, A. C., Schulz, J. B., Brown, R. H., Jr., and Beal, M. F., 1993, Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis, J. Neurochem. 61:2322–2325.PubMedCrossRefGoogle Scholar
  13. Brady, S., 1995, Interfering with the runners, Nature 375:12–13.PubMedCrossRefGoogle Scholar
  14. Brown, R. H., Jr., 1995, Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice, Cell 80:687–692.PubMedCrossRefGoogle Scholar
  15. Brownell, B., Oppenheimer, D. R., and Hughes, J. T., 1970, The central nervous system in motor neurone disease, J. Neurol. Neurosurg. Psych. 33:338–357.CrossRefGoogle Scholar
  16. Carlioz, A., and Touati, D., 1986, Isolation of superoxide dismutase mutants in Escherichia coli: Is superoxide dismutase necessary for aerobic life?, EMBO J. 5:623–630.PubMedGoogle Scholar
  17. Carpenter, S., 1968, Proximal axonal enlargement in motor neuron disease, Neurology 18:841–851.PubMedCrossRefGoogle Scholar
  18. Card, M. T., Battistoni, A., Polizio, F., Desideri, A., and Rotilio, G., 1994, Impaired copper binding by the H46R mutant of human Cu,Zn superoxide dismutase, involved in amyotrophic lateral sclerosis, FEBS Lett. 356:314–316.CrossRefGoogle Scholar
  19. Chang, E. C., and Kosman, D. J., 1990, O2-dependent methionine auxotrophy in Cu,Zn superoxide dismutase-deficient mutants of Saccharomyces cerevisiae, J. Bacteriol. 172:1840–1845.Google Scholar
  20. Chary, P., Dillon, D., Schroeder, A. L., and Natvig, D. O., 1994, Superoxide dismutase sod-1 null mutants of Neurospora crassna: Oxidative stress sensitivity, spontaneous mutation rate and response to mutagens, Genetics 137:723–730.PubMedGoogle Scholar
  21. Chou, S. M., 1992, Pathology-light microscopy of amyotrophic lateral sclerosis, in: Handbook of Amyotrophic Lateral Sclerosis (R. A. Smith, ed.), Marcel Dekker, New York, p. 133.Google Scholar
  22. Cizewski-Culotta, V., Joh, H.-D., Lin, S.-J., Hudak-Slekar, K., and Strem, J., 1995, A physiological role for saccharomyces cerevisice copper/zinc superoide dismutase in copper buffering, J. Biol. Chem. 270:29991–29997.CrossRefGoogle Scholar
  23. Cleveland, D. W., Laing, N., Hurse, P. V., and Brown, R. H., Jr., 1995, Toxic mutants in Charcot’s sclerosis, Nature 378:342.PubMedCrossRefGoogle Scholar
  24. Coyle, J. T., and Puttfarcken, P., 1993, Oxidative stress, glutamate, and neurodegenerative disorders, Science 262:689–695.PubMedCrossRefGoogle Scholar
  25. Dameron, C. T., and Harris, E. D., 1987, Regulation of aortic CuZn-superoxide dismutase with copper. Caeruloplasmin and albumin re-activate and transfer copper to the enzyme in culture, Biochem. J. 248:669–675.PubMedGoogle Scholar
  26. Delisle, M. B., and Carpenter, S., 1984, Neurofibrillary axonal swellings and amyotrophic lateral sclerosis, J. Neurol. Sci. 63, 241–250.PubMedCrossRefGoogle Scholar
  27. Deng, H.-X., Hentati, A., Tainer, J. A., Iqbal, Z., Cayabyab, A., Hung, W.-Y., Getzoff, E. D., Hu, P., Herzfeldt, B., Roos, R. P., Warner, C., Deng, G., Soriano, E., Smyth, C., Parge, H. E., Ahmed, A., Roses, A. D., Hallewell, R. A., Pericak-Vance, M. A., and Siddique, T., 1993, Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase, Science 261:1047–1051.PubMedCrossRefGoogle Scholar
  28. Dexter, D., Carter, C., Agid, F., Agid, Y, Lees, A. J., Jenner, P., and Marsden, C. D., 1986, Lipid peroxidation as cause of nigral cell death in Parkinson’s disease, Lancet 2:639–640.PubMedCrossRefGoogle Scholar
  29. DiSilvestro, R. A., 1989, Copper activation of superoxide dismutase in rat erythrocytes, Arch. Biochem. Biophys. 274:298–303.PubMedCrossRefGoogle Scholar
  30. Elshafey, A., Lanyon, W. G., and Connor, J. M., 1994, Identification of a new missense point mutation in exon 4 of the Cu/Zn superoxide dismutase SOD-1 gene in a family with amyotrophic lateral sclerosis, Hum. Mol. Genetics 3:363–364.CrossRefGoogle Scholar
  31. Enayat, Z. E., Orrell, R. W., Claus, A., Ludolph, A., Bachus, R., Brockmüller, J., Ray-Chaudhuri, K., Radunovic, A., Shaw, C., Wilkinson, J., King, A., Swash, M., Leigh, P. N., de Belleroche, J., and Powell, J., 1995, Two novel mutations in the gene for copper zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis, Hum. Mol. Genet. 4:1239–1240.PubMedCrossRefGoogle Scholar
  32. Engelhardt, J. I., Siklös, L., Komuves, L., Smith, R. G., and Appel, S. H., 1995, Antibodies to calcium channels from ALS patients passively transferred to mice selectively increase intracellular calcium and induce ultrastructural changes in motoneurons, Synapse 20:185–199.PubMedCrossRefGoogle Scholar
  33. Fair, S. B., D’Ari, R., and Touati, D., 1986, Oxygen-dependent mutagenesis in Escherichia coli lacking superoxide dismutase, Proc. Natl. Acad. Sci. USA 83:8268–8272.CrossRefGoogle Scholar
  34. Freedman, J. H., and Peisach, J., 1989, Intracellular copper transport in cultured hepatoma cells, Biochem. Biophys. Res. Commun. 164:134–140.PubMedCrossRefGoogle Scholar
  35. Fridovich, I., 1986, Superoxide dismutases, Adv. Enzymol. Relat. Areas Mol. Biol. 58:61–97.PubMedGoogle Scholar
  36. Fujii, J., Myint, T., Seo, H. G., Kayanoki, Y, Ikeda, Y, and Taniguchi, N., 1995, Characterization of wild-type and amyotrophic lateral sclerosis-related mutant Cu,Zn superoxide dismutases overproduced in baculovirus-infected insect cells, J. Neurochem. 64:1456–1461.PubMedCrossRefGoogle Scholar
  37. Gonatas, N. K., Stieber, A., Mourelatos, Z., Chen, Y., Gonatas, J. O., Appel, S. H., Hays, A. P., Hickey, W. F., and Hauw, J.-J., 1992, Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis, Am. J. Pathol 140:731–737.PubMedGoogle Scholar
  38. Gopinath, C., and Howell, J. M., 1975, Experimental chronic copper toxicity in sheep. Changes that follow the cessation of dosing at the onset of haemolysis, Res. Vet. Sci. 19:35–43.PubMedGoogle Scholar
  39. Greenlund, L. J. S., Deckwerth, T. L., and Johnson, E. M., Jr., 1995, Superoxide dismutase delays neuronal apoptosis: A role for reactive oxygen species in programmed neuronal death, Neuron 14:303–315.PubMedCrossRefGoogle Scholar
  40. Gurney, M. E., 1994, Mutant mice, Cu,Zn superoxide dismutase, and motor neuron degeneration, Science 266:1587.PubMedCrossRefGoogle Scholar
  41. Gurney, M. E., Pu, H., Chiu, A. Y, Dal Canto, M. C., Polchow, C. Y, Alexander, D. D., Caliendo, J., Hentati, A., Kwon, Y W., Deng, H.-X., Chen, W., Zhai, P., Sufit, R. L., and Siddique, T., 1994, Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation, Science 264:1772–1775.PubMedCrossRefGoogle Scholar
  42. Hajimohammadreza, I., and Brammer, M., 1990, Brain membrane fluidity and lipid peroxidation in Alzheimer’s disease, Neurosci. Lett. 112:333–337.PubMedCrossRefGoogle Scholar
  43. Halliwell, B., 1992, Oxygen radicals as key mediators in neurological disease: Fact or fiction, Ann. Neurol. 32:S10-S15.CrossRefGoogle Scholar
  44. Harding, A. E., 1993, Inherited neuronal atrophy and degeneration predominantly of lower motor neurons, in: Peripheral Neuropathy (P. J. Dyck, P. K. Thomas, J. W. Griffin, P. A. Low, and J. F. Poduslo, eds.), W. B. Saunders, Philadelphia, pp. 1051–1064.Google Scholar
  45. Harris, E. D., 1992, Copper as a cofactor and regulator of copper, zinc superoxide dismutase, J. Nutr. 122:636–640.PubMedGoogle Scholar
  46. Harris, E. D., and Percival, S. S., 1989, Copper transport: Insights into a ceruloplasmin-based delivery system, Adv. Exp. Med. Biol. 258:95–102.PubMedGoogle Scholar
  47. Haverkamp, L. J., Appel, V., and Appel, S. H., 1995, Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction, Brain 118:707–719.PubMedCrossRefGoogle Scholar
  48. Hendrickson, D. J., Fisher, J. H., Jones, C., and Ho, Y.-S., 1990, Regional localization of human extracellular superoxide dismutase gene to 4pter-q21, Genomics 8:736–738.PubMedCrossRefGoogle Scholar
  49. Hirano, A., Malamud, N., Kurland, L. T., and Zimmerman, H. M., 1969, A review of the pathologic findings in amyotrophic lateral sclerosis, in: Motor Neuron Diseases. Research on Amyotrophic Lateral Sclerosis and Other Disorders (F. H. Norris and L. T. Kurland, eds.), Grune & Stratton, New York, pp. 51–60.Google Scholar
  50. Hirano, A., 1973, Progress in the pathology of motor neuron diseases, in: Progress in Neuropathology (H. M. Zimmerman, ed.), Grune & Stratton, New York, pp. 181–215.Google Scholar
  51. Hirano, A., 1984, Neuropathology of ALS, in: Amyotrophic Lateral Sclerosis in Asia and Oceania (K. M. Chen and Y Yase, eds.), Shyan-Fu Chou, Taiwan, pp. 23–30.Google Scholar
  52. Hirano, A., 1991, Cytopathology of amyotrophic lateral sclerosis, in: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases (L. P. Rowland, ed.), Raven Press, New York, pp. 91–101.Google Scholar
  53. Hirano, A., and Kato, S., 1992, Fine structural study of sporadic and familial amyotrophic lateral sclerosis, in: Handbook of Amyotrophic Lateral Sclerosis (R. A. Smith, ed.), Marcel Dekker, New York, pp. 183— 192.Google Scholar
  54. Hirano, A., Donnenfeld, H., Sasaki, S., and Nakano, I., 1984, Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis, J. Neuropathol. Exp. Neurol. 43:461–470.PubMedCrossRefGoogle Scholar
  55. Hirano, M., Fujii, J., Nagai, Y, Sonobe, M., Okamoto, K., Araki, H., Taniguchi, N., and Ueno, S., 1994, A new variant Cu/Zn superoxide dismutase Val7 → Glu deduced from lymphocyte mRNA sequences from Japanese patients with familial amyotrophic lateral sclerosis, Biochem. Biophys. Res. Commun. 204:572–577.PubMedCrossRefGoogle Scholar
  56. Howell, J. M., Blakemore, W. F., Gopinath, C., Hall, G. A., and Parker, J. H., 1974, Chronic copper poisoning and changes in the central nervous system of sheep, Acta Neuropathol. Berl. 29:9–24.PubMedCrossRefGoogle Scholar
  57. Ikeda, M., Abe, K., Aoki, M., Sahara, M., Watanabe, M., Shoji, M., St. George-Hyslop, P. H., Hirai, S., and Itoyama, Y., 1995, Variable clinical symptoms in familial amyotrophic lateral sclerosis with a novel point mutation in the Cu/Zn superoxide dismutase gene, Neurology 45:2038–2042.PubMedCrossRefGoogle Scholar
  58. Imlay, J. A., and Linn, S., 1988, DNA damage and oxygen radical toxicity, Science 240:1302–1309.PubMedCrossRefGoogle Scholar
  59. Jordan, J., Ghadge, G. D., Prehn, J. H., Toth, P. T., Roos, R. P., and Miller, R. J., 1995, Expression of human copper/zinc-superoxide dismutase inhibits the death of rat sympathetic neurons caused by withdrawal of nerve growth factor, Mol Pharmacol. 47:1095–1100.PubMedGoogle Scholar
  60. Kato, S., Oda, M., and Hayashi, H., 1993, Neuropathology in amyotrophic lateral sclerosis patients on respirators: uniformity and diversity in 13 cases, Neuropathology 13:229–236.CrossRefGoogle Scholar
  61. Kawamata, J., Hasegawa, H., Shimohama, S., Kimura, J., Tanaka, S., and Ueda, K., 1994, Leu106 → Val CTC → GTC mutation of superoxide dismutase-1 gene in patient with familial amyotrophic lateral sclerosis in Japan, Lancet 343:1501.PubMedCrossRefGoogle Scholar
  62. Kostrzewa, M., Burck-Lehmann, U., and Muller, U., 1994, Autosomal dominant amyotrophic lateral sclerosis: A novel mutation in the Cu/Zn superoxide dismutase-1 gene, Hum. Mol. Genet. 3:2261–2262.PubMedCrossRefGoogle Scholar
  63. Kuncl, R. W., Crawford, T. O., Rothstein, J. D., and Drachman, D. B., 1992, Motor neuron diseases, in: Diseases of the Nervous System (A. K. Asbury, G. M. McKhann and W. I. McDonald, eds.), W. B. Saunders, Philadelphia, pp. 1179–1208.Google Scholar
  64. Kurtzke, J. F., 1991, Risk factors in amyotrophic lateral sclerosis, in: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases (L. P. Rowland, ed.), Raven Press, New York, pp. 245–270.Google Scholar
  65. Lapinskas, P. J., Cunningham, K. W., Liu, X. F., Fink, G. R., and Cizewski-Culotta, V, 1995, Mutations in PMR1 suppress oxidative damage in yeast cells lacking superoxide dismutase, Mol. Cell. Biol. 15:1382–1388.PubMedGoogle Scholar
  66. Lee, M. K., and Cleveland, D. W., 1994, Neurofilament function and dysfunction: Involvement in axonal growth and neuronal disease, Curr. Opin. Cell Biol. 6:34–40.PubMedCrossRefGoogle Scholar
  67. Leigh, P. N., 1994, Pathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disorders, in: Neurodegenerative Diseases (D. B. Calne, ed.), W. B. Saunders, Philadelphia, pp. 473–488.Google Scholar
  68. Levieux, A., Levieux, D., and Lab, C., 1991, Immunoquantitation of rat erythrocyte superoxide dismutase: Its use in copper deficiency, Free Radic. Biol. Med. 11:589–595.PubMedCrossRefGoogle Scholar
  69. Liu, X. F., and Cizewski-Culotta, V, 1994, The requirement for yeast superoxide dismutase is bypassed through mutations in BSD2, a novel metal homeostasis gene, Mol. Cell Biol. 14:7037–7045.PubMedGoogle Scholar
  70. Lowe, J., 1994, New pathological findings in amyotrophic lateral sclerosis, J. Neurol. Sci. 124:38–51.PubMedCrossRefGoogle Scholar
  71. Lowe, J., Mayer, R. J., and Landon, M., 1993, Ubiquitin in neurodegenerative diseases, Brain Pathol. 3:55–65.PubMedCrossRefGoogle Scholar
  72. Manetto, V, Sternberger, N. H., Perry, G., Sternberger, L. A., and Gambetti, P., 1988, Phosphorylation of neurofilaments is altered in amyotrophic lateral sclerosis, J. Neuropathol Exp. Neurol. 47:642–653.PubMedCrossRefGoogle Scholar
  73. Matsumoto, S., Kusaka, H., Murakami, N., Hashizume, Y, Okazaki, H., and Hirano, A., 1992, Basophilic inclusions in sporadic juvenile amyotrophic lateral sclerosis: An immunocytochemical and ultrastructural study, Acta Neuropathol 83:579–583.PubMedCrossRefGoogle Scholar
  74. McCord, J. M., 1994, Mutant mice, Cu,Zn superoxide dismutase, and motor neuron degeneration, Science 266:1586–1587.PubMedGoogle Scholar
  75. Mcintosh, L. J., Trush, M. A., and Troncoso, J. C., 1991, Oxygen-free radical mediated processes in Alzheimer’s disease, Soc. Neurosci. Abstr. 17:1071 (abstract).Google Scholar
  76. Mecocci, P., MacGarvey, U., Kaufman, A. E., Koontz, D., Shoffner, J. M., Wallace, D. C., and Beal, M. F., 1993, Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain, Ann. Neurol. 34:609–616.PubMedCrossRefGoogle Scholar
  77. Munoz, D. G., Greene, C., Perl, D. P., and Selkoe, D. J., 1988, Accumulation of phosphorylated neurofilaments in anterior horn motoneurons of amyotrophic lateral sclerosis patients, J. Neuropathol. Exp. Neurol 47:9–18.PubMedCrossRefGoogle Scholar
  78. Nakano, R., Sato, S., Inuzuka, T., Sakimura, K., Mishina, M., Takahashi, H., Ikuta, F., Honma, Y, Fujii, J., Taniguchi, N., and Tsuji, S., 1994, A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis, Biochem. Biophys. Res. Commun. 200:695–703.PubMedCrossRefGoogle Scholar
  79. Olanow, C. W., 1993, A radical hypothesis for neurodegeneration, Trends Neurosci. 16:439–444.PubMedCrossRefGoogle Scholar
  80. Oppenheimer, D. R., and Esiri, M. M., 1992, Diseases of the basal ganglia, cerebellum and motor neurons, in: Greenfield’s Neuropathology (J. H. Adams and L. W. Duchen, eds.), Oxford University Press, New York, p. 988.Google Scholar
  81. Orr, W. C., and Sohal, R. S., 1994, Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster, Science 263:1128–1130.Google Scholar
  82. Orrell, R., de Belleroche, J., Marklund, S., Bowe, F., and Hallewell, R., 1995, A novel SOD mutant and ALS, Nature 374:504–505.PubMedCrossRefGoogle Scholar
  83. Pardo, C. A., Xu, Z., Borchelt, D. R., Price, D. L., Sisodia, S. S., and Cleveland, D. W., 1995, Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons, Proc. Natl Acad. Sci. USA 92:954–958.PubMedCrossRefGoogle Scholar
  84. Parge, H. E., Hallewell, R. A., and Tainer, J. A., 1992, Atomic structures of wild-type and thermostable mutant recombinant human Cu,Zn superoxide dismutase, Proc. Natl. Acad. Sci. USA 89:6109–6113.PubMedCrossRefGoogle Scholar
  85. Percival, S. S., and Harris, E. D., 1989, Ascorbate enhances copper transport from ceruloplasmin into human K562 cells, J. Nutr. 119:779–784.PubMedGoogle Scholar
  86. Percival, S. S., Bae, B., and Patrice, M., 1993, Copper is required to maintain Cu/Zn-superoxide dismutase activity during HL-60 cell differentiation, Proc. Soc. Exp. Biol. Med. 203:78–83.PubMedGoogle Scholar
  87. Phillips, J. P., Campbell, S. D., Michaud, D., Charbonneau, M., and Hilliker, A. J., 1989, Null mutation of copper/zinc superoxide dismutase in Drosophila confers hypersensitivity to paraquat and reduced longevity, Proc. Natl. Acad. Sci. USA 86:2761–2765.PubMedCrossRefGoogle Scholar
  88. Phillips, J. P., Tainer, J. A., Getzoff, E. D., Boulianne, G. L., Kirby, K., and Hilliker, A. J., 1995, Subunit- destabilizing mutations in Drosophila copper/zinc superoxide dismutase: Neuropathology and a model of dimer dysequilibrium, Proc. Natl. Acad. Sci. USA 92:8574–8578.PubMedCrossRefGoogle Scholar
  89. Pogun, S., Dawson, V., and Kuhar, M., 1994, Nitric oxide inhibits 3H-glutamate transport in synaptosomes, Synapse 18:21–26.PubMedCrossRefGoogle Scholar
  90. Pramatarova, A., Goto, J., Nanba, E., Nakashima, K., Takahashi, K., Takagi, A., Kanazawa, I., Figlewicz, D. A., and Rouleau, G. A., 1994, A two basepair deletion in the SOD 1 gene causes familial amyotrophic lateral sclerosis, Hum. Mol. Genet. 3:2061–2062.PubMedGoogle Scholar
  91. Price, D. L., Borchelt, D. R., Walker, L. C., and Sisodia, S. S., 1992a, Toxicity of synthetic Aß peptides and modeling of Alzheimer’s disease, Neurobiol. Aging 13:623–625.PubMedCrossRefGoogle Scholar
  92. Price, D. L., Martin, L. J., Clatterbuck, R. E., Koliatsos, V. E., Sisodia, S. S., Walker, L. C., and Cork, L. C, 1992b, Neuronal degeneration in human diseases and animal models, J. Neurobiol. 23:1277–1294.PubMedCrossRefGoogle Scholar
  93. Rabizadeh, S., Butler-Gralla, E., Borchelt, D. R., Gwinn, R., Selverstone-Valentine, J., Sisodia, S., Wong, P., Lee, M., Hahn, H., and Bredesen, D. E., 1995, Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: Studies in yeast and neural cells, Proc. Natl. Acad. Sci. USA 92:3024–3028.PubMedCrossRefGoogle Scholar
  94. Rainero, L, Pinessi, L., Tsuda, T., Vignocchi, M. G., Vaula, G., Calvi, L., Cerrato, P., Rossi, B., Bergamini, L., McLachlan, D. R. C., and St. George-Hyslop, P. H., 1994, SOD1 missense mutation in an Italian family with ALS, Neurology 44:347–349.PubMedCrossRefGoogle Scholar
  95. Reveillaud, I., Phillips, J., Duyf, B., Hilliker, A., Kongpachith, A., and Fleming, J. E., 1994, Phenotypic rescue by a bovine transgene in a Cu/Zn superoxide dismutase-null mutant of Drosophila melanogaster, Mol. Cell. Biol. 14:1302–1307.PubMedGoogle Scholar
  96. Ripps, M. E., Huntley, G. W, Hof, P. R., Morrison, J. H., and Gordon, J. W., 1995, Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis, Proc. Natl. Acad. Sci. USA 92:689–693.PubMedCrossRefGoogle Scholar
  97. Robberecht, W, Sapp, P., Viaene, M. K., Rosen, D., McKenna-Yasek, D., Haines, J., Horvitz, R., Theys, P., and Brown, R., Jr., 1994, Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis, J. Neurochem. 62:384–387.PubMedCrossRefGoogle Scholar
  98. Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O’Regan, J. P., Deng, H.-X., Rahmani, Z., Krizus, A., McKenna-Yasek, D., Cayabyab, A., Gaston, S. M., Berger, R., Tanzi, R. E., Halperin, J. J., Herzfeldt, B., Van den Bergh, R., Hung, W.-Y, Bird, T., Deng, G., Mulder, D. W, Smyth, C., Laing, N. G., Soriano, E., Pericak-Vance, M. A., Haines, J., Rouleau, G. A., Gusella, J. S., Horvitz, H. R., and Brown, R. H., Jr., 1993, Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature 362:59–62.PubMedCrossRefGoogle Scholar
  99. Rothstein, J. D., and Kuncl, R. W., 1995, Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity, J. Neurochem. 65:643–651.PubMedCrossRefGoogle Scholar
  100. Rothstein, J. D., Martin, L. J., and Kuncl, R. W., 1992, Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis, N. Engl. J. Med. 326:1464–1468.PubMedCrossRefGoogle Scholar
  101. Rothstein, J. D., Jin, L., Dykes-Hoberg, M., and Kuncl, R. W., 1993, Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity, Proc. Natl. Acad. Sci. USA 90:6591–6595.PubMedCrossRefGoogle Scholar
  102. Rothstein, J. D., Bristol, L. A., Hosier, B., Brown, R. H., Jr., and Kuncl, R. W., 1994a, Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons, Proc. Natl. Acad. Sci. USA 91:4155–4159.PubMedCrossRefGoogle Scholar
  103. Rothstein, J. D., Martin, L., Dykes-Hoberg, M., Jin, L., Levey, A., and Kuncl, R. W., 1994b, Glutamate transporter subtypes: Role in excitotoxicity and amyotrophic lateral sclerosis, Ann. Neurol. 36:282 (abstract).Google Scholar
  104. Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J., and Kuncl, R. W., 1995, Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis, Ann. Neurol. 38:73–84.PubMedCrossRefGoogle Scholar
  105. Rowland, L. R, 1994a, Natural history and clinical features of amyotrophic lateral sclerosis and related motor neuron diseases, in: Neurodegenerative Diseases (D. B. Calne, ed.), W. B. Saunders, Philadelphia, pp. 507–521.Google Scholar
  106. Rowland, L. R, 1994b, Amyotrophic lateral sclerosis: theories and therapies, Ann. Neurol. 35:129–130.PubMedCrossRefGoogle Scholar
  107. Sapp, R C., Rosen, D. R., Hosier, B. A., Esteban, J., Mckennayasek, D., Oregan, J. P., Horvitz, H. R., and Brown, R. H., 1995, Identification of three novel mutations in the gene for Cu/Zn superoxide dismutase in patients with familial amyotrophic lateral sclerosis, Neuromusc. Disord. 5:353–357.PubMedCrossRefGoogle Scholar
  108. Sasaki, S., Kamei, H., Yamane, K., and Maruyama, S., 1988, Swelling of neuronal processes in motor neuron disease, Neurology 38:1114–1118.PubMedCrossRefGoogle Scholar
  109. Schmidt, M. L., Carden, M. J., Lee, V. M.-Y., and Trojanowski, J. Q., 1987, Phosphate dependent and independent neurofilament epitopes in the axonal swellings of patients with motor neuron disease and controls, Lab. Invest. 56:282–294.PubMedGoogle Scholar
  110. Siddique, T., Pericak-Vance, M. A., Brooks, B. R., Roos, R. P., Hung, W.-Y, Antel, J. P., Munsat, T. L., Phillips, K., Warner, K., Speer, M., Bias, W. B., Siddique, N. A., and Roses, A. D., 1989, Linkage analysis in familial amyotrophic lateral sclerosis, Neurology 39:919–925.PubMedCrossRefGoogle Scholar
  111. Siddique, T., Figlewicz, D. A., Pericak-Vance, M. A., Haines, J. L., Rouleau, G., Jeffers, A. J., Sapp, P., Hung, W.-Y, Bebout, J., McKenna-Yasek, D., Deng, G., Horvitz, H. B., Gusella, J. F., Brown, R. H., Jr., Roses, A. D., Roos, R. P., Williams, D. B., Mulder, D. W., Watkins, P. C., Noore, R., Nicholson, G., Reed, R., Brooks, B. R., Festoff, B., Antel, J. P., Tandan, R., Munsat, T. L., Laing, N. G., Halperin, J. J., Norris, F. H., Van den Bergh, R., Swerts, L., Tanzi, R. E., Jubelt, B., Mathews, K. D., and Bosch, E. P., 1991, Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity, N. Engl. J. Med. 324:1381–1384.PubMedCrossRefGoogle Scholar
  112. Smith, R. A., 1992, Handbook of Amyotrophic Lateral Sclerosis, Marcel Dekker, New York.Google Scholar
  113. Smith, R. G., and Appel, S. H., 1995, Molecular approaches to amyotrophic lateral sclerosis, Annu. Rev. Med. 46:133–145.PubMedCrossRefGoogle Scholar
  114. Stadtman, E. R., 1990, Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences, Free Radic. Biol. Med. 9:315–325.PubMedCrossRefGoogle Scholar
  115. Stadtman, E. R., 1992, Protein oxidation and aging, Science 257:1220–1224.PubMedCrossRefGoogle Scholar
  116. Stadtman, E. R., and Oliver, C. N., 1991, Metal-catalyzed oxidation of proteins, J. Biol. Chem. 266:2005–2008.PubMedGoogle Scholar
  117. Steinkuhler, C., Sapora, O., Carri, M. T., Nagel, W., Marcocci, L., Ciriolo, M. R., Weser, U, and Rotilio, G., 1991, Increase of Cu,Zn-superoxide dismutase activity during differentiation of human K562 cells involves activation by copper of a constantly expressed copper-deficient protein, J. Biol. Chem. 266:24580–24587.PubMedGoogle Scholar
  118. Steinkuhler, C., Carri, M. T., Micheli, G., Knoepfel, L., Weser, U., and Rotilio, G., 1994, Copper-dependent metabolism of Cu,Zn-superoxide dismutase in human K562 cells. Lack of specific transcriptional activation and accumulation of a partially inactivated enzyme, Biochem. J. 302:687–694.PubMedGoogle Scholar
  119. Subbarao, K. V, Richardson, J. S., and Ang, L. C., 1990, Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J. Neurochem. 55:342–345.PubMedCrossRefGoogle Scholar
  120. Tandan, R., and Bradley, W. G., 1985a, Amyotrophic lateral sclerosis: Part 1 Clinical features, pathology, and ethical issues in management, Ann. Neurol. 18:271–280.PubMedCrossRefGoogle Scholar
  121. Tandan, R., and Bradley, W. G., 1985b, Amyotrophic lateral sclerosis: Part 2. Etiopathogenesis. Ann. Neurol. 18:419–431.PubMedCrossRefGoogle Scholar
  122. Troy, C. M., and Shelanski, M. L., 1994, Down-regulation of copper/zinc superoxide dismutase causes apoptotic death in PC 12 neuronal cells, Proc. Natl. Acad. Sci. USA 91:6384–6387.PubMedCrossRefGoogle Scholar
  123. Tsuda, T., Munthasser, S., Fraser, P. E., Percy, M. E., Rainero, I., Vaula, G., Pinessi, L., Bergamini, L., Vignocchi, G., McLachlan, D. R. C., Tatton, W. G., and St. George-Hyslop, P., 1994, Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis, Neuron 13:727–736.PubMedCrossRefGoogle Scholar
  124. Uauy, R., Castillo-Duran, C., Fisberg, M., Fernandez, N., and Valenzuela, A., 1985, Red cell superoxide dismutase activity as an index of human copper nutrition, J. Nutr. 115:1650–1655.PubMedGoogle Scholar
  125. Volterra, A., Trotti, D., Cassutti, P., Tromba, C., Salvaggio, A., Melcangi, R. C., and Racagni, G., 1992, High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes, J. Neurochem. 59:600–606.PubMedCrossRefGoogle Scholar
  126. Volterra, A., Trotti, D., Tromba, C., Floridi, S., and Racagni, G., 1994, Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes, J. Neurosci. 14:2924–2932.PubMedGoogle Scholar
  127. Wiedau-Pazos, M., Goto, J. J., Rabizadeh, S., Gralla, E. B., Roe, J. A., Lee, M. K., Valentine, J. S., and Bredesen, D. E., 1996, Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis, Science 271:515–518.PubMedCrossRefGoogle Scholar
  128. Williams, D. B., and Windebank, A. J., 1993, Motor neuron disease, in: Peripheral Neuropathy (P. J. Dyck, P. K. Thomas, J. W. Griffin, P. A. Low, and J. F. Poduslo, eds.), W. B. Saunders, Philadelphia, pp. 1028–1050.Google Scholar
  129. Wong, P. C., and Borchelt, D. R., 1995, Motor neuron disease caused by mutations in superoxide dismutase 1. Curr. Opin. Neurol. 8:294–301.PubMedCrossRefGoogle Scholar
  130. Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., Sisodia, S. S., Cleveland, D. W, and Price, D. L., 1995, An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria, Neuron 14:1105–1116.PubMedCrossRefGoogle Scholar
  131. Yan, S.-D., Chen, X., Schmidt, A.-M., Brett, J., Godman, G., Zou, Y.-S., Scott, C. W, Caputo, C., Frappier, T., Smith, M. A., Perry, G., Yen, S.-H., and Stern, D., 1994, Glycated tau protein in Alzheimer disease: A mechanism for induction of oxidant stress, Proc. Natl. Acad. Sci. USA 91:7787–7791.PubMedCrossRefGoogle Scholar
  132. Yim, M. B., Chock, PB., and Stadtman, E. R., 1990, Copper,zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide, Proc. Natl. Acad. Sci. USA 87:5006–5010.PubMedCrossRefGoogle Scholar
  133. Yim, M. B., Chock, P. B., and Stadtman, E. R., 1993, Enzyme function of copper,zinc superoxide dismutase as a free radical generator, J. Biol. Chem. 268:4099–4105.PubMedGoogle Scholar
  134. Young, A. B., 1990, What’s the excitement about excitatory amino acids in amyotrophic lateral sclerosis?, Ann. Neurol. 28:9–11.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • David R. Borchelt
    • 1
  • Philip C. Wong
    • 1
  • Mark W. Becher
    • 1
  • Lucie I. Bruijn
    • 2
  • Don W. Cleveland
    • 2
  • Neal G. Copeland
    • 3
  • Valeria C. Culotta
    • 4
  • Nancy A. Jenkins
    • 3
  • Michael K. Lee
    • 1
  • Carlos A. Pardo
    • 1
  • Donald L. Price
    • 5
  • Sangram S. Sisodia
    • 1
  • Zhou-Shang Xu
    • 2
  1. 1.Department of Pathology and the Neuropathology LaboratoryThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA
  2. 2.Department of Biological ChemistryThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA
  3. 3.Mammalian Genetics Laboratory, ABL-Basic Research ProgramNCI-Frederick Cancer Center Research and DevelopmentFrederickUSA
  4. 4.Departments of Biochemistry and Environmental Health SciencesThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA
  5. 5.Departments of Pathology, Neurology, and Neuroscience, and the Neuropathology LaboratoryThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA

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