Skip to main content
SpringerLink
Log in

SOD1 gene mutations in patients with amyotrophic lateral sclerosis: Potential of method of molecular modeling

  • Structural and Functional Analysis of Biopolymers and Their Complexes
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Molecular modeling is a promising method for assessing protein structures that is capable of presenting an energetically beneficial protein conformation with atomic precision. This method is of great importance for studying molecular interactions and confirming the pathogenic significance of the changes in protein structures caused by particular mutations. In this study, we used molecular modeling to assess mutations in the SOD1 gene in patients with amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder characterized by the loss of spinal and cerebral motor neurons. The product of SOD1 is a cytosolic dimeric enzyme Cu/Zn superoxide dismutase (SOD1) responsible for the detoxification of cellular superoxide radicals. We showed that all eight revealed coding-point mutations of the gene led to moderate or significant changes in SOD1 protein energy. The mutation His49Arg increased protein energy, and the reconstruction of the respective model indicated the spatial destabilization of the molecule and abnormal interactions with the metal ion inside the active center. Conversely, the other seven mutations (Gly17Ala, Leu85Val, Asn87Ser, Asp91Ala, Ser106Leu, Glu134Gly, and Leu145Phe) led to a decrease in protein energy and an increase in the spatial stability of SOD 1, which is usually accompanied by an increased tendency for the inert mutant molecule to misfold and demonstrate cellular aggregation. Therefore, the results of the in silico analysis of the SOD1 gene mutations confirms that ALS belongs to the class of the so-called conformational diseases of the central nervous system, a characteristic feature of which is the formation of cytotoxic, insoluble protein inclusions in neurons.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ALS:

amyotrophic lateral sclerosis

SOD1:

cytosolic Cu/Zn-superoxide dismutase

References

  1. Chiti F., Stefani M., Taddei N., Ramponi G., Dobson C.M. 2003. Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature. 424(6950), 805–808.

    Article  PubMed  CAS  Google Scholar 

  2. Padhi A.K., Kumar H., Vasaikar S.V., Jayaram B., Gomes J. 2012. Mechanisms of loss of functions of human angiogenin variants implicated in amyotrophic lateral sclerosis. PLoS ONE. 7(2), e32479.

    Article  PubMed  CAS  Google Scholar 

  3. Sierra Bello O., Gonzalez J., Capani F., Barreto G.E. 2012. In silico docking reveals possible Riluzole binding sites on Nav1.6 sodium channel: implications for amyotrophic lateral sclerosis therapy. J. Theor. Biol. 315, 53–63.

    Article  PubMed  CAS  Google Scholar 

  4. Garden D.P., Zhorov B.S. 2010. Docking flexible ligands in proteins with a solvent exposure- and distance-dependent dielectric function. J. Comput. Aided Mol. Des. 24(2), 91–105.

    Article  PubMed  CAS  Google Scholar 

  5. Zavalishin I.A. 2009. Bokovoi amiotroficheskii skleroz (Amyotrophic Lateral Sclerosis). Moscow: GEOTAR-Media.

    Google Scholar 

  6. Illarioshkin S.N. 2007. Genetics. In: Bokovoi amiotroficheskii skleroz (Amyotrophic Lateral Sclerosis). Zavalishin I.A., Ed., Moscow: Evraziya, pp. 230–255.

    Google Scholar 

  7. Brown J.A., Min J., Staropoli J.F., Collin E., Bi S., Feng X., Barone R., Cao Y., O’Malley L., Xin W., Mullen T.E., Sims K.B. 2012. SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a United States clinical testing lab experience. Amyotroph. Lateral. Scler. 13(2), 217–222.

    Article  PubMed  CAS  Google Scholar 

  8. Millecamps S., Salachas F., Cazeneuve C., Gordon P., Bricka B., Camuzat A., Guillot-Noël L., Russaouen O., Bruneteau G., Pradat P.F., Le Forestier N., Vandenberghe N., Danel-Brunaud V., Guy N., Thauvin-Robinet C., Lacomblez L., Couratier P., Hannequin D., Seilhean D., Le Ber I., Corcia P., Camu W., Brice A., Rouleau G., LeGuern E., Meininger V. 2010. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: Genotype-phenotype correlations. J. Med. Genet. 47(8), 554–560.

    Article  PubMed  CAS  Google Scholar 

  9. http://www.ncbi.nlm.nih.gov/books/NBK1450/

  10. Mackenzie I.R.A., Rademakers R., Neumann M. 2010. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9(10), 995–1007

    Article  PubMed  CAS  Google Scholar 

  11. Rosen D.R., Siddique T., Patterson D., Figlewicz D.A., Sapp P., Hentati A., Donaldson D., et al. 1993. Mutations in Cu/Zn su-peroxide dismutase are associated with familial amyotrophic lateral sclerosis. Nature. 362, 59–62.

    Article  PubMed  CAS  Google Scholar 

  12. http://string-db.org/

  13. Julien J.-P. 2001. Amyotrophic lateral sclerosis: Unfolding the toxicity of the misfolded. Cell. 104, 581–591.

    Article  PubMed  CAS  Google Scholar 

  14. Illarioshkin S.N. 2003. Konformatsionnye bolezni mozga (Conformational Diseases of the Brain). Moscow: Yanus-K.

    Google Scholar 

  15. http://www.uniprot.org/

  16. Weiner J., Kollman P.A., Case D.A., Singh U.C., Chio C., Alagona G., Profeta S., Weiner P.K. 1984. A new force field for molecular mechanical simulation of nucleic acids and proteins. J. Am. Chem. Soc. 106, 765–784.

    Article  CAS  Google Scholar 

  17. Li Z., Scheraga H.A. 1987. Monte Carlo-minimization approach to the multiple-minima problem in protein folding. Proc. Natl. Acad. Sci. U. S. A. 84, 6611–6615.

    Article  PubMed  CAS  Google Scholar 

  18. http://www.zmmsoft.com/

  19. Illarioshkin S.N. 2004. DNK-diagnostika i medikogeneticheskoe konsul’tirovanie (DNA Diagnosis and Medical Genetic Consulting). Moscow: MIA.

    Google Scholar 

  20. Aoki M., Abe K., Houi K., Ogasawara M., Matsubara Y., Kobayashi T., Mochio S., Narisawa K., Itoyama Y. 1995. Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel Cu/Zn superoxide dismutase mutation. Ann. Neurol. 37, 676–679.

    Article  PubMed  CAS  Google Scholar 

  21. 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., et al. 1993. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science. 261(5124), 1047–1051.

    Article  PubMed  CAS  Google Scholar 

  22. Andersen P.M., Nilsson P., Ala-Hurula V., Keranen M.-L., Tarvainen I., Haltia T., Nilsson L., Binzer M., Forsgren L., Marklund S.L. 1995. Amyotrophic lateral sclerosis associated with homozygosity for an asp90-to-ala mutation in CuZn-superoxide dismutase. Nature Genet. 10, 61–66.

    Article  PubMed  CAS  Google Scholar 

  23. Skovronsky D.M., Lee V.M., Trojanowski J.Q. 2006. Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu. Rev. Pathol. 1, 151–170.

    Article  PubMed  CAS  Google Scholar 

  24. Shelkovnikova T.A., Kulikova A.A., Tsvetkov Ph.O., Peters O., Bachurin S.O., Buchman V.L., Ninkina N.N. 2012. Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology. Mol. Biol. (Moscow). 46, 362–374.

    Article  CAS  Google Scholar 

  25. Ross C.A., Tabrizi S.J. 2011. Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83–98.

    Article  PubMed  CAS  Google Scholar 

  26. Rubinsztein D.C. 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 443, 780–786.

    Article  PubMed  CAS  Google Scholar 

  27. Zakharova M.N. 2007. Etiology and pathogenesis. In: Bokovoi amiotroficheskii skleroz (Amyotrophic Lateral Sclerosis). Zavalishin I.A. Ed. Moscow: Evraziya.

    Google Scholar 

  28. Leinweber B., Barofsky E., Barofsky D.F., Ermilov V., Nylin K., Beckman J.S. 2004. Aggregation of ALS mutant superoxide dismutase expressed in Escherichia coli. Free Radic. Biol. Med. 36(7), 911–918.

    Article  PubMed  CAS  Google Scholar 

  29. Stathopulos P.B., Rumfeldt J.A., Scholz G.A., Irani R.A., Frey H.E., Hallewell R.A., Lepock J.R., Meiering E.M. 2003. Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc. Natl. Acad. Sci. U. S. A. 100(12), 7021–7026.

    Article  PubMed  CAS  Google Scholar 

  30. Ermilova I.P., Ermilov V.B., Levy M., Ho E., Pereira C., Beckman J.S. 2005. Protection by dietary zinc in ALS mutant G93A SOD transgenic mice. Neurosci. Lett. 379(1), 42–46.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, 125367, Russia

    E. V. Lysogorskaia, A. V. Rossokhin, N. Yu. Abramycheva, M. N. Zakharova & S. N. Illarioshkin

Authors
  1. E. V. Lysogorskaia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. V. Rossokhin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Yu. Abramycheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. N. Zakharova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. N. Illarioshkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. V. Lysogorskaia.

Additional information

Original Russian Text © E.V. Lysogorskaia, A.V. Rossokhin, N.Yu. Abramycheva, M.N. Zakharova, S.N. Illarioshkin, 2013, published in Molekulyarnaya Biologiya, 2013, Vol. 47, No. 5, pp. 861–867.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lysogorskaia, E.V., Rossokhin, A.V., Abramycheva, N.Y. et al. SOD1 gene mutations in patients with amyotrophic lateral sclerosis: Potential of method of molecular modeling. Mol Biol 47, 751–757 (2013). https://doi.org/10.1134/S0026893313050129

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893313050129

Keywords

Search

Navigation