Skip to main content
SpringerLink
Log in

Monitoring systemic oxidative stress in an animal model of amyotrophic lateral sclerosis

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

A mutant form of the ubiquitous copper/zinc superoxide dismutase (SOD1) protein has been found in some patients with amyotrophic lateral sclerosis (ALS). We monitored oxidative stress in an animal model of ALS, the SODG93A mouse, which develops a disease similar to ALS with an accelerated course. The aim of this work was to show that ALS damages several organs and tissues, from an oxidative stress point of view. We measured lipid and protein oxidative damage in different tissue homogenates of SODG93A mice. The biomarkers that we analyzed were malondialdehyde + 4-hydroxyalkenal (MDA + 4-HDA) and carbonyls, respectively. The spinal cord and brain of SODG93A mice showed increased lipid peroxidation after 100 or 130 days compared to age-matched littermate controls. The CNS was most affected, but lipid peroxidation was also detected in the skeletal muscle and liver on day 130. No changes were observed in protein carbonylation in the homogenates. Our results are consistent with a multisystem etiology of ALS and suggest that oxidative stress may play a primary role in ALS pathogenesis. Thus, oxidative stress represents a potential biomarker that might be useful in developing new therapeutic strategies for ALS.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Agar J, Durham H (2003) Relevance of oxidative injury in the pathogenesis of motor neuron diseases. Amyotroph Lateral Scler Other Motor Neuron Disord 4:232–242

    Article  PubMed  CAS  Google Scholar 

  2. Aguirre N, Beal MF, Matson WR, Bogdanov MB (2005) Increased oxidative damage to DNA in an animal model of amyotrophic lateral sclerosis. Free Radic Res 39:383–388

    Article  PubMed  CAS  Google Scholar 

  3. Andrus PK, Fleck TJ, Gurney ME, Hall ED (1998) Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 71:2041–2048

    Article  PubMed  CAS  Google Scholar 

  4. Asai H, Hirano M, Udaka F, Shimada K, Oda M, Kubori T, Nishinaka K, Tsujimura T, Izumi Y, Konishi N, Matsumoto S, Kameyama M, Ueno S (2007) Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS. J Neurol Sci 254:78–83

    Article  PubMed  Google Scholar 

  5. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  6. Brooks KJ, Hill MD, Hockings PD, Reid DG (2004) MRI detects early hindlimb muscle atrophy in Gly93Ala superoxide dismutase-1 (G93A SOD1) transgenic mice, an animal model of familial amyotrophic lateral sclerosis. NMR Biomed 17:28–32

    Article  PubMed  Google Scholar 

  7. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338

    Article  PubMed  CAS  Google Scholar 

  8. Cheeseman KH, Slater TF (1993) An introduction to free radical biochemistry. Br Med Bull 49:481–493

    PubMed  CAS  Google Scholar 

  9. Chiu AY, Zhai P, Dal Canto MC, Peters TM, Kwon YW, Prattis SM, Gurney ME (1995) Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Mol Cell Neurosci 6:349–362

    Article  PubMed  CAS  Google Scholar 

  10. Ciriza J, Moreno-Igoa M, Calvo AC, Yague G, Palacio J, Miana-Mena FJ, Munoz MJ, Zaragoza P, Brulet P, Osta R (2008) A genetic fusion GDNF-C fragment of tetanus toxin prolongs survival in a symptomatic mouse ALS model. Restor Neurol Neurosci 26:459–465

    PubMed  CAS  Google Scholar 

  11. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117

    Article  PubMed  CAS  Google Scholar 

  12. Cleveland DW (1999) From Charcot to SOD1: mechanisms of selective motor neuron death in ALS. Neuron 24:515–520

    Article  PubMed  CAS  Google Scholar 

  13. Corcia P, Pradat PF, Salachas F, Bruneteau G, Forestier N, Seilhean D, Hauw JJ, Meininger V (2008) Causes of death in a post-mortem series of ALS patients. Amyotroph Lateral Scler 9:59–62

    Article  PubMed  Google Scholar 

  14. Dal Canto MC, Gurney ME (1995) Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu, Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res 676:25–40

    Article  PubMed  CAS  Google Scholar 

  15. Davies KJ, Delsignore ME, Lin SW (1987) Protein damage and degradation by oxygen radicals. II. Modification of amino acids. J Biol Chem 262:9902–9907

    PubMed  CAS  Google Scholar 

  16. Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP et al (1993) Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261:1047–1051

    Article  PubMed  CAS  Google Scholar 

  17. Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S, Belia S, Wannenes F, Nicoletti C, Del Prete Z, Rosenthal N, Molinaro M, Protasi F, Fano G, Sandri M, Musaro A (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8:425–436

    Article  PubMed  CAS  Google Scholar 

  18. Dupuis L, di Scala F, Rene F, de Tapia M, Oudart H, Pradat PF, Meininger V, Loeffler JP (2003) Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. FASEB J 17:2091–2093

    PubMed  CAS  Google Scholar 

  19. Ferrante RJ, Shinobu LA, Schulz JB, Matthews RT, Thomas CE, Kowall NW, Gurney ME, Beal MF (1997) Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. Ann Neurol 42:326–334

    Article  PubMed  CAS  Google Scholar 

  20. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20:2534–2542

    PubMed  CAS  Google Scholar 

  21. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97–112

    Article  PubMed  CAS  Google Scholar 

  22. Genova ML, Pich MM, Bernacchia A, Bianchi C, Biondi A, Bovina C, Falasca AI, Formiggini G, Castelli GP, Lenaz G (2004) The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann NY Acad Sci 1011:86–100

    Article  PubMed  CAS  Google Scholar 

  23. Gil J, Funalot B, Verschueren A, Danel-Brunaud V, Camu W, Vandenberghe N, Desnuelle C, Guy N, Camdessanche JP, Cintas P, Carluer L, Pittion S, Nicolas G, Corcia P, Fleury MC, Maugras C, Besson G, Le Masson G, Couratier P (2008) Causes of death amongst French patients with amyotrophic lateral sclerosis: a prospective study. Eur J Neurol 15:1245–1251

    Article  PubMed  CAS  Google Scholar 

  24. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX 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 

  25. Hall ED, Andrus PK, Oostveen JA, Fleck TJ, Gurney ME (1998) Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS. J Neurosci Res 53:66–77

    Article  PubMed  CAS  Google Scholar 

  26. Halliwell B, Aruoma OI (1991) DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett 281:9–19

    Article  PubMed  CAS  Google Scholar 

  27. Halliwell B, Gutteridge JM (1999) Free radicals, ‘‘reactive species’’ and toxicology. In: Editor OU (ed) Free radicals in biology and medicine. Oxford University Press, New York, pp 544–616

  28. Jokic N, Di Scala F, Dupuis L, Rene F, Muller A, Gonzalez De Aguilar JL, Loeffler JP (2003) Early activation of antioxidant mechanisms in muscle of mutant Cu/Zn-superoxide dismutase-linked amyotrophic lateral sclerosis mice. Ann NY Acad Sci 1010:552–556

    Article  PubMed  CAS  Google Scholar 

  29. Jonsson PA, Bergemalm D, Andersen PM, Gredal O, Brannstrom T, Marklund SL (2008) Inclusions of amyotrophic lateral sclerosis-linked superoxide dismutase in ventral horns, liver, and kidney. Ann Neurol 63:671–675

    Article  PubMed  CAS  Google Scholar 

  30. Kanner J, German JB, Kinsella JE (1987) Initiation of lipid peroxidation in biological systems. Crit Rev Food Sci Nutr 25:317–364

    Article  PubMed  CAS  Google Scholar 

  31. Leclerc N, Ribera F, Zoll J, Warter JM, Poindron P, Lampert E, Borg J (2001) Selective changes in mitochondria respiratory properties in oxidative or glycolytic muscle fibers isolated from G93AhumanSOD1 transgenic mice. Neuromuscul Disord 11:722–727

    Article  PubMed  CAS  Google Scholar 

  32. Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357

    Article  PubMed  CAS  Google Scholar 

  33. Lino MM, Schneider C, Caroni P (2002) Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neurosci 22:4825–4832

    PubMed  CAS  Google Scholar 

  34. Mahoney DJ, Kaczor JJ, Bourgeois J, Yasuda N, Tarnopolsky MA (2006) Oxidative stress and antioxidant enzyme upregulation in SOD1-G93A mouse skeletal muscle. Muscle Nerve 33:809–816

    Article  PubMed  CAS  Google Scholar 

  35. Miana-Mena FJ, Munoz MJ, Yague G, Mendez M, Moreno M, Ciriza J, Zaragoza P, Osta R (2005) Optimal methods to characterize the G93A mouse model of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 6:55–62

    Article  PubMed  CAS  Google Scholar 

  36. Moges H, Vasconcelos OM, Campbell WW, Borke RC, McCoy JA, Kaczmarczyk L, Feng J, Anders JJ (2009) Light therapy and supplementary Riboflavin in the SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis (FALS). Lasers Surg Med 41:52–59

    Article  PubMed  Google Scholar 

  37. Orrell RW (2000) Amyotrophic lateral sclerosis: copper/zinc superoxide dismutase (SOD1) gene mutations. Neuromuscul Disord 10:63–68

    Article  PubMed  CAS  Google Scholar 

  38. Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA (2001) Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21:3369–3374

    PubMed  CAS  Google Scholar 

  39. Puttaparthi K, Wojcik C, Rajendran B, DeMartino GN, Elliott JL (2003) Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes. J Neurochem 87:851–860

    Article  PubMed  CAS  Google Scholar 

  40. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr, Scott RW, Snider WD (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47

    Article  PubMed  CAS  Google Scholar 

  41. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  PubMed  CAS  Google Scholar 

  42. Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, Simeoni S, Crippa V, Onesto E, Palazzolo I, Rusmini P, Bolzoni E, Bendotti C, Poletti A (2007) Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet 16:1604–1618

    Article  PubMed  CAS  Google Scholar 

  43. Shaw IC, Fitzmaurice PS, Mitchell JD, Lynch PG (1995) Studies on cellular free radical protection mechanisms in the anterior horn from patients with amyotrophic lateral sclerosis. Neurodegeneration 4:391–396

    Article  PubMed  CAS  Google Scholar 

  44. Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH (2004) Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 62:1758–1765

    PubMed  CAS  Google Scholar 

  45. Turner BJ, Lopes EC, Cheema SS (2003) Neuromuscular accumulation of mutant superoxide dismutase 1 aggregates in a transgenic mouse model of familial amyotrophic lateral sclerosis. Neurosci Lett 350:132–136

    Article  PubMed  CAS  Google Scholar 

  46. Weydt P, Hong S, Witting A, Moller T, Stella N, Kliot M (2005) Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival. Amyotroph Lateral Scler Other Motor Neuron Disord 6:182–184

    Article  PubMed  CAS  Google Scholar 

  47. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (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

    Article  PubMed  CAS  Google Scholar 

  48. Zhou C, Zhao CP, Zhang C, Wu GY, Xiong F (2007) A method comparison in monitoring disease progression of G93A mouse model of ALS. Amyotroph Lateral Scler 8:366–372

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Universidad de Zaragoza (UZ2007-BIO-11), the Gobierno de Aragón (Aging and Oxidative Stress Physiology, Grant No. B40), the Instituto de Estudios Altoaragoneses, funds from the Fondo de Investigación Sanitaria of Spain (PI071133) and the Project Tú eliges: tú decides of Caja de Ahorros de Navarra in Spain. The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Departamento Farmacología y Fisiología, Universidad de Zaragoza, c) Domingo Miral s/n, 50009, Zaragoza, Spain

    Francisco Javier Miana-Mena, Cristina González-Mingot, María Jesús Muñoz, Lorena Fuentes-Broto, Enrique Martínez-Ballarín & Joaquín José García

  2. Neurology Service, Universitary Hospital Lozano Blesa of Zaragoza, Zaragoza, Spain

    Cristina González-Mingot & Pilar Larrodé

  3. LAGENBIO, Universidad de Zaragoza, Zaragoza, Spain

    María Jesús Muñoz, Sara Oliván & Rosario Osta

  4. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, USA

    Russel J. Reiter

Authors
  1. Francisco Javier Miana-Mena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina González-Mingot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pilar Larrodé
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María Jesús Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sara Oliván
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lorena Fuentes-Broto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Enrique Martínez-Ballarín
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Russel J. Reiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rosario Osta
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joaquín José García
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joaquín José García.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miana-Mena, F.J., González-Mingot, C., Larrodé, P. et al. Monitoring systemic oxidative stress in an animal model of amyotrophic lateral sclerosis. J Neurol 258, 762–769 (2011). https://doi.org/10.1007/s00415-010-5825-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-010-5825-8

Keywords

Search

Navigation