Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions

Nature Genetics volume 15, pages 91–94 (1997)Cite this article

Abstract

A subset of familial and sporadic amyotrophic lateral sclerosis (ALS — a fatal disorder characterised by progressive motor neuron degeneration) cases are due to mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1)1–4. Two mutations which have been successfully used to generate transgenic mice that develop an ALS-like syndrome are glycine 85 to arginine (G85R) and glycine 93 to alanine (G93A) with the mutant SOD7 allele overexpressed in a normal mouse genetic background5–7. No ALS-like phenotype is observed in mice overexpressing wild-type SOD1 or mice without any SOD1 activity6,8,9. These dominant mutations, which do not necessarily decrease SOD1 activity, may confer a gain of function that is selectively lethal to motor neurons5,10–12. The yeast interaction trap system⊃13 allowed us to determine whether these mutations in SOD7 caused novel protein interactions not observed with wild-type SOD7 and which might participate in the generation of the ALS phenotype. Two proteins, lysyl-tRNA synthetase and translocon-associated protein delta, interact with mutant forms of SOD1 but not with wild-type SOD1. The specificity of the interactions was confirmed by the coimmunoprecipitation of mutant SOD1 and the expressed proteins. These proteins are expressed in ventral cord, lending support to the relevance of this interaction to motor neuron disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Rosen, D.R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Pramatarova, A. et al. Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis. Am. J. Hum. Genet. 56, 592–596 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Jones, C.T., Brock, D.J.H., Chancellor, A.M., Warlow, C.P. & Swingler, R.J. Cu/Zn superoxide dismutase (SOD1) mutations and sporadic amyotrophic lateral sclerosis. Lancet 342, 1050–1051 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Swingler, R.J., Jones, C. & Brock, D.J.H. Superoxide dismutase and amyotrophic lateral sclerosis. Lancet 345, 391 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Gurney, M.E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Dal Canto, M.C. & Gurney, M.E. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am. J. Pathol. 146, 1271–1279 (1994).

    Google Scholar 

  7. Ripps, M.E., Huntley, G.W., Hof, P.R., Morrison, J.H. & Gordon, J.W. 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 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan, P.H., Chu, L., Chen, S.F., Carlson, E.J. & Epstein, C.J. Reduced neurotoxicity in transgenic mice overexpressing human copper-zinc-superoxide dismutase. Stroke 21, 111(80)–111(82) (1990).

    Google Scholar 

  9. Reaume, A.G. et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nature Genet. 13, 43–47 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Fujii, J. et al. 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 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Tsuda, T. et al. Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis. Neuron 13, 727–736 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Borchelt, D.R. et al. 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 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Finley, R.L. Jr & Brent, R. Interaction trap cloning with yeast. in Gene Probes —A practical approach (Oxford University Press, 1984).

  14. Rabizadeh, S. et al. 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 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hallewell, R.A. et al. Genetically engineered polymers of human CuZn superoxide dismutase: biochemistry and serum half-lives. J. Biol. Chem. 264, 5260–5268 (1989).

    CAS  PubMed  Google Scholar 

  16. Hartmann, E. et al. A tetrameric complex of membrane proteins in the endoplasmic reticulum. Eur. J. Biochem. 214, 375–381 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Targoff, I.N., Trieu, E.P. & Miller, F.W. Reaction of Anti-OJ autoantibodies with components of the multi-enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase. J. Clin. Invest. 91, 2556–2564 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gelpi, C., Martinez, M.A., Vidal, S., Targoff, I.N. & Rodriguez-Sanchez, J.L. Autoantibodies to a transfer RNA-associated protein in a murine model of chronic graft versus host disease. J. Immunol. 152, 1989–1999 (1994).

    CAS  PubMed  Google Scholar 

  19. Gelin, C. et al. The E2 antigen, a 32 kd glycoprotein involved in T-cell adhesion processes, in the MIC2 gene product. EMBO J. 8, 3253–3259 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Online Mendelian Inheritance in Man, OMIM (TM). Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 1996. World Wide Web URL: http://www3.ncbi.nlm.nih.gov/omim/

  21. Freist, W. & Gauss, D.H. Lysyl-tRNA synthetase. Biol. Chem. Hoppe-Seyler 376, 451–472 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Pardo, C.A. et al. 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 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rosen, D.R. et al. A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis. Hum. Mol. Genet. 3, 981–987 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Holthuis, J.C.M., van Riel, M.C.H.M. & Martens, G.J.M. Translocon-associated protein TRAP5 and a novel TRAP-like protein are coordinately expressed with pro-opiomelanocortin in Xenopus intermediate pituitary. Biochem. J. 312, 205–213 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wiedau-Pazos, M. et al. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 271, 515–518 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Yim, M.B. et al. 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 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mourelatos, Z., Gonatas, N.K., Stieber, A., Gurney, M.E. & Dal Canto, M.C., Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc Natl. Acad. Sci. USA 93, 5472–5477 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, X.-J. et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398–402 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Burke, J.R. et al. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 2, 347–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Sikorski, R.S. & Hieter, P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics 122, 19–27 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bermingham-McDonogh, O., Gralla, E.B. & Selverstone Valentine, J. The copper, zinc-superoxide dismutase gene of Saccharomyces cerevisiae: cloning, sequencing, and biological activity. Proc. Natl. Acad. Sci. USA 85, 4789–4793 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Eleanor Roosevelt Institute for Cancer Research,

    Catherine B. Kunst & David Patterson

  2. Human Medical Genetics Program and Departments of Biochemistry, Biophysics and Genetics and Medicine of the University of Colorado Health Science Center, 1899 Gaylord Street, Denver, Colorado, 80206, USA

    Catherine B. Kunst & David Patterson

  3. laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland, 20892, USA

    Eva Mezey & Michael J. Brownstein

Authors
  1. Catherine B. Kunst
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Mezey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael J. Brownstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kunst, C., Mezey, E., Brownstein, M. et al. Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions. Nat Genet 15, 91–94 (1997). https://doi.org/10.1038/ng0197-91

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0197-91

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing