Skip to main content
SpringerLink
Log in

Copper-Zinc Superoxide Dismutase and ALS

  • Chapter
Copper Transport and Its Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 448))

Abstract

Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is a neurodegenerative disorder characterized by the slow loss of large motor neurons in the spinal cord and brain. The mean age of onset is 55 years. After the disease begins, it progresses relentlessly to a lethal paralysis and culminates in the death of the afflicted person, usually within two to five years of symptom onset (Brown, 1997). The disease is inherited in approximately 10 % of cases and about one-fifth of those familial ALS (FALS) cases are associated with dominantly inherited, single-site mutations in SOD1, the gene that encodes human copper-zinc Superoxide dismutase (CuZnSOD) (Cudkowicz and Brown, 1996). SOD-associated FALS thus represents only a fraction of the total cases of ALS, but it is the only form of the disease for which a cause is known. Many laboratories are actively seeking to understand how mutations in CuZnSOD cause this form of ALS in the hope that such knowledge will hasten the discovery of causes of this disease as well as potential therapeutic agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Bannister, J. V., Bannister, W. H., and Rotilio, G. (1987). Aspects of the structure, function, and applications of superoxide dismutase. CRC Crit. Rev. Biochem. 22, 111–180.

    Article  PubMed  CAS  Google Scholar 

  • Beal, M. F., Ferrante, R. J., Browne, S. E., Matthews, R. T., Kowall, N. W., and Brown, R. H., Jr. (1997). Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42, 644–654.

    Article  PubMed  CAS  Google Scholar 

  • Beckman, J. S., Carson, M., Smith, C. D., and Koppenol, W. H. (1993). ALS, SOD and peroxynitrite. Nature 364, 584.

    Article  PubMed  CAS  Google Scholar 

  • Bertini, I., Banci, L., and Piccioli, M. (1990). Spectroscopic studies on Cu2Zn2SOD: A continuous advancement of investigation tools. Coord. Chem. Rev. 100, 67–103.

    Article  CAS  Google Scholar 

  • Borchelt, D. R., Lee, M. K., Slunt, H. S., 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.

    Article  CAS  Google Scholar 

  • Brown, R. H., Jr. (1997). Amyotrophic lateral sclerosis. Arch. Neurol. 54, 1246–1250.

    Article  PubMed  Google Scholar 

  • Bruijn, L. T., Beal, M. F., Becher, M. W., Schulz, J. B., Wong, P. C., Price, D. L., and Cleveland, D. W. (1997). Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease, implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked Superoxide dismutase 1 mutant. Proc. Natl. Acad. Sci. (USA) 94, 7606–7611.

    Article  CAS  Google Scholar 

  • Bruijn, L. I., and Cleveland, D. W. (1996). Mechanisms of selective motor neuron death in ALS: Insights from transgenic mouse models of motor neuron disease. Neuropathol. Appl. Neurobiol. 22, 373–387.

    Article  PubMed  CAS  Google Scholar 

  • Carri, M. T., Ferri, A., Battistoni, A., Famhy, L., Gabbianelli, R., Poccia, F., and Rotilio, G. (1997). Expression of a Cu, Zn Superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial al-teration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells. FEBS Lett. 414, 365–368.

    Article  PubMed  CAS  Google Scholar 

  • Cleveland, D. W., Bruijn, L. L, Wong, P. C., Marszalek, J. R., Vechio, J. D., Lee, M. K., Xu, X. S., Borchelt, D. R., Sisodia, S. S., and Price, D. L. (1996). Mechanisms of selective motor neuron death in transgenic mouse models of motor neuron disease. Neurology 47, 54–62.

    Article  Google Scholar 

  • Crow, J. P., Sampson, J. B., Zhuang, Y., Thompson, J. A., and Beckman, J. S. (1997). Decreased zinc affinity of amyotrophic lateral sclerosis-associated Superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J. Neurochem. 69, 1936–1944.

    Article  PubMed  CAS  Google Scholar 

  • Cudkowicz, M. E., and Brown, R. H., Jr. (1996). An update on Superoxide dismutase 1 in familial amyotrophic lateral sclerosis. J. Neurol. Sci. 139, 10–15.

    Article  PubMed  Google Scholar 

  • Dal Canto, M. C., and Gurney, M. E. (1997). A low expressor line of transgenic mice carrying a mutant human Cu, Zn Superoxide dismutase (SOD1) gene develops pathological changes that most closely resemble those in human amyotrophic lateral sclerosis. Acta Neuropathol. (Berlin) 93, 537–550.

    Article  Google Scholar 

  • 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., and et al. (1993). Amyotrophic lateral sclerosis and structural defects in Cu, Zn Superoxide dismutase. Science 261, 1047–1051.

    Article  PubMed  CAS  Google Scholar 

  • Durham, H. D., Roy, J., Dong, L., and Figlewicz, D. A. (1997). Aggregation of mutant Cu/Zn Superoxide dismutase proteins in a culture model of ALS. J. Neuropathol. Exp. Neurol. 56, 523–530.

    Article  PubMed  CAS  Google Scholar 

  • Ferrante, R. J., Browne, S. E., Shinobu, L. A., Bowling, A. C, Baik, M. J., MacGarvey, U., Kowall, N. W., Brown, R. H., Jr., and Beal, M. F. (1997). Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J. Neurochem. 69, 2064–2074.

    Article  PubMed  CAS  Google Scholar 

  • Fridovich, I. (1997). Superoxide anion radical (O2), Superoxide dismutases, and related matters. J. Biol. Chem. 272, 18515–18517.

    Article  PubMed  CAS  Google Scholar 

  • Gralla, E. B. (1997). Superoxide Dismutase: Studies in the Yeast Saccharomyces Cerevisiae. In Oxidative Stress and the Molecular Biology of Antioxidant Defenses, J. Scandalios, ed. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press), pp. 495–525.

    Google Scholar 

  • Gralla, E. B., and Kosman, D. (1992). Molecular genetics of Superoxide dismutases in yeasts and related fungi. Adv. Genet. 30,251–319.

    Article  PubMed  CAS  Google Scholar 

  • Gurney, M. E. (1997). Transgenic animal models of familial amyotrophic lateral sclerosis. J. Neurol. 244Suppl 2, S15–20.

    Article  PubMed  Google Scholar 

  • Gurney, M. E., Cutting, F. B., Zhai, P., Doble, A., Taylor, C. P., Andrus, P. K., and Hall, E. D. (1996). Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. 39, 147–157.

    Article  PubMed  CAS  Google Scholar 

  • 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., and et al. (1994). Motor neuron degeneration in mice that express a human Cu, Zn Superoxide dismutase mutation. Science 264, 1772–1775.

    Article  PubMed  CAS  Google Scholar 

  • Hallewell, R. A., Mills, R., Tekamp-Olson, P., Blacher, R., Rosenberg, S., Otting, F., Masiarz, F. R., and Scandella, C. J. (1987). Amino terminal acylation of authentic human Cu, Zn Superoxide dismutase produced in yeast. Bio/Technology 5, 363–366.

    Article  CAS  Google Scholar 

  • Hart, P. J., Hart, P. J., Liu, H., Pellegrini, M., Nersissian, A. M., Gralla, E. B., Valentine, J. S., and Eisenberg, D. (1998). Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in fa-milial amyotrophic lateral sclerosis. Protein Science (in press).

    Google Scholar 

  • Hottinger, A. F., Fine, E. G., Gurney, M. E., Zum, A. D., and Aebischer, P. (1997). The copper chelator d-penicil-lamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. Eur. J. Neurosci. 9, 1548–1551.

    Article  PubMed  CAS  Google Scholar 

  • Juneja, T., Pericak-Vance, M. A., Laing, N. G., Dave, S., and Siddique, T. (1997). Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu 100gly and ala4val mutations in Cu, Zn Superoxide dismutase. Neurology 48, 55–57.

    Article  PubMed  CAS  Google Scholar 

  • Kunst, C. B., Mezey, E., Brownstein, M. J., and Patterson, D. (1997). Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions. Nat. Genet. 15, 91–94.

    Article  PubMed  CAS  Google Scholar 

  • Liochev, S. I., Chen, L. L., Hallewell, R. A., and Fridovich, I. (1997). Superoxide-dependent peroxidase activity of H48Q: a Superoxide dismutase variant associated with familial amyotrophic lateral sclerosis. Arch. Biochem. Biophys. 346, 263–268.

    Article  PubMed  CAS  Google Scholar 

  • Lyons, T. J., Liu, H., Goto, J. J., Nersissian, A., Roe, J. A., Graden, J. A., Cafe, C., Ellerby, L. M., Bredesen, D. E., Gralla, E. B., and Valentine, J. S. (1996). Mutations in copper-zinc Superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein. Proc. Natl. Acad. Sci. (USA) 93, 12240–12244.

    Article  CAS  Google Scholar 

  • Nishida, C. R., Gralla, E. B., and Valentine, J. S. (1994). Characterization of three yeast copper-zinc Superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. (USA) 91, 9906–9910.

    Article  CAS  Google Scholar 

  • Ogihara, N. L., Parge, H. E., Hart, P. J., Weiss, M. S., Goto, J. J., Crane, B. R., Tsang, J., Slater, K., Roe, J. A., Valentine, J. S., Eisenberg, D., and Tainer, J. A. (1996). Unusual trigonal-planar copper configuration revealed in the atomic structure of yeast copper-zinc Superoxide dismutase. Biochemistry 35, 2316–2321.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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. Acad. Sci. (USA) 89, 6109–6113.

    Article  CAS  Google Scholar 

  • Rabizadeh, S., Gralla, E. B., Borcheit, D. R., Gwinn, R., Valentine, J. S., 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.

    Article  CAS  Google Scholar 

  • Reaume, A. G., Elliot, J. L., Hoffman, E. K., Kowall, N. W., Ferrante, R. J., Siwek, D. F., Wilcox, H. M., Flood, D. G., Beal, M. F., Jr., R. H. B., Scott, R. W., and Snider, W. D. (1996). Motor neurons in Cu/Zn Superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat. Genet. 13, 43–51.

    Article  PubMed  CAS  Google Scholar 

  • 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 Jr., R. H. (1993). Mutations in Cu/Zn Superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62.

    Article  PubMed  CAS  Google Scholar 

  • Siddique, T., and Deng, H. X. (1996). Genetics of amyotrophic lateral sclerosis. Hum. Mol. Genet. 5 Spec No, 1465–1470.

    PubMed  CAS  Google Scholar 

  • Tainer, J. A., Getzoff, E. D., Beem, K. M., Richardson, J. S., and Richardson, D. C. (1982). Determination and analysis of the 2 A structure of copper, zinc Superoxide dismutase. J. Mol. Biol. 160, 181.

    Article  PubMed  CAS  Google Scholar 

  • Tainer, J. A., Getzoff, E. D., Richardson, J. S., and Richardson, D. C. (1983). Structure and mechanism of copper, zinc Superoxide dismutase. Nature 306, 284–287.

    Article  PubMed  CAS  Google Scholar 

  • Tu, P. H., Gurney, M. E., Julien, J. P., Lee, V. M., and Trojanowski, J. Q. (1997). Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. Lab. Invest. 76, 441–456.

    PubMed  CAS  Google Scholar 

  • Valentine, J. S. (1994). Dioxygen Reactions. In Bioinorganic Chemistry, I. Bertini, H. B. Gray, S. J. Lippard and J. S. Valentine, eds. (Mill Valley, California: University Science Books) pp. 253–314.

    Google Scholar 

  • Valentine, J. S., and Pantoliano, M. W. (1981). Protein-metal ion interactions in cuprozinc protein (superoxide dismutase): A major intracellular repository for copper and zinc in the eukaryotic cell. In Copper Proteins, T. G. Spiro, ed.: John Wiley and Sons, Inc.), pp. 292–358.

    Google Scholar 

  • Valentine, J. S., Wertz, D. L., Lyons, T. J., Liou, L.-L., Goto, J. J., and Gralla, E. B. (1998). The dark side of dioxygen biochemistry. Curr. Op. Chem. Biol. (in press).

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Williamson, T. L., Marszalek, J. R., Vechio, J. D., Bruijn, L. I., Lee, M. K., Xu, Z., Brown, R. H., Jr., and Cleveland, D. W. (1996). Neurofilaments, radial growth of axons, and mechanisms of motor neuron disease. Cold Spring Harb. Symp. Quant. Biol. 61, 709–723.

    Article  PubMed  CAS  Google Scholar 

  • Yim, H. S., Kang, J. PL, Chock, P. B., Stadtman, E. R., and Yim, M. B. (1997). A familial amyotrophic lateral sclerosis-associated A4V Cu, Zn-superoxide dismutase mutant has a lower Km for hydrogen peroxide. Correlation between clinical severity and the Km value. J. Biol. Chem. 272, 8861–8863.

    Article  PubMed  CAS  Google Scholar 

  • Yim, M. B., Chock, P. B., and Stadtman, E. R. (1990). Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc. Natl. Acad. Sci. (USA) 87, 5006–5010.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Yim, M. B., Kang, J. H., Yim, H. S., Kwak, H. S., Chock, P. B., and Stadtman, E. R. (1996). A gain-of-function of an amyotrophic lateral sclerosis-associated Cu, Zn-superoxide dismutase mutant: An enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc. Natl. Acad. Sci. (USA) 93, 5709–5714.

    Article  CAS  Google Scholar 

  • Zhang, B., Tu, P., Abtahian, F., Trojanowski, J. Q., and Lee, V. M. (1997). Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J. Cell. Biol. 139, 1307–1315.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, UCLA, Los Angeles, California, 90095-1569, USA

    Joan Selverstone Valentine, P. John Hart & Edith Butler Gralla

Authors
  1. Joan Selverstone Valentine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. John Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edith Butler Gralla
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Salerno, Salerno, Italy

    Arturo Leone

  2. The Murdoch Institute for Research into Birth Defects, Royal Children’s Hospital, Parkville, Australia

    Julian F. B. Mercer

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media New York

About this chapter

Cite this chapter

Valentine, J.S., Hart, P.J., Gralla, E.B. (1999). Copper-Zinc Superoxide Dismutase and ALS. In: Leone, A., Mercer, J.F.B. (eds) Copper Transport and Its Disorders. Advances in Experimental Medicine and Biology, vol 448. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4859-1_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4859-1_17

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7204-2

  • Online ISBN: 978-1-4615-4859-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation