Journal of Molecular Neuroscience

, Volume 38, Issue 2, pp 94–102 | Cite as

DJ-1 Changes in G93A-SOD1 Transgenic Mice: Implications for Oxidative Stress in ALS

  • Nirit Lev
  • Debby Ickowicz
  • Yael Barhum
  • Eldad Melamed
  • Daniel Offen


Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder. The causes of ALS are still obscure. Accumulating evidence supports the hypothesis that oxidative stress and mitochondrial dysfunction can be implicated in ALS pathogenesis. DJ-1 plays an important role in the oxidative stress response. The aim of this study was to discover whether there are changes in DJ-1 expression or in DJ-1-oxidized isoforms in an animal model of ALS. We used mutant SOD1G93A transgenic mice, a commonly used animal model for ALS. Upregulation of DJ-1 mRNA and protein levels were identified in the brains and spinal cords of SOD1G93A transgenic mice as compared to wild-type controls, evident from an early disease stage. Furthermore, an increase in DJ-1 acidic isoforms was detected, implying that there are more oxidized forms of DJ-1 in the CNS of SOD1G93A mice. This is the first report of possible involvement of DJ-1 in ALS. Since DJ-1 has a protective role against oxidative stress, it may suggest a possible therapeutic target in ALS.


Amyotrophic lateral sclerosis (ALS) DJ-1 Cu/Zn superoxide dismutase (SOD1) Oxidative stress 


  1. Abe, K., Pan, L. H., Watanabe, M., Kato, T., & Itoyama, Y. (1995). Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. Neuroscience Letters, 199, 152–154. doi: 10.1016/0304-3940(95)12039-7.PubMedCrossRefGoogle Scholar
  2. Abe, K., Pan, L. H., Watanabe, M., Konno, H., Kato, T., & Itoyama, Y. (1997). Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis. Neurological Research, 19, 124–128.PubMedGoogle Scholar
  3. Agar, J., & Durham, H. (2003). Relevance of oxidative injury in the pathogenesis of motor neuron diseases. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 4, 232–242. doi: 10.1080/14660820310011278.PubMedCrossRefGoogle Scholar
  4. Aguirre, N., Beal, M. F., Matson, W. R., & Bogdanov, M. B. (2005). Increased oxidative damage to DNA in an animal model of amyotrophic lateral sclerosis. Free Radical Research, 39, 383–388. doi: 10.1080/10715760400027979.PubMedCrossRefGoogle Scholar
  5. Andrus, P. K., Fleck, T. J., Gurney, M. E., & Hall, E. D. (1998). Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. Journal of Neurochemistry, 71, 2041–2048.PubMedGoogle Scholar
  6. Annesi, G., Savettieri, G., Pugliese, P., et al. (2005). DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. Annals of Neurology, 58, 803–807. doi: 10.1002/ana.20666.PubMedCrossRefGoogle Scholar
  7. Aoyama, K., Matsubara, K., Fujikawa, Y., et al. (2000). Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitritemediated oxidative stress in neurodegenerative diseases. Annals of Neurology, 47, 524–527. doi: 10.1002/1531-8249(200004)47:4<524::AID-ANA19>3.0.CO;2-5.PubMedCrossRefGoogle Scholar
  8. Bader, V., Ran Zhu, X., Lubbert, H., & Stichel, C. C. (2005). Expression of DJ-1 in the adult mouse CNS. Brain Research, 1041, 102–111. doi: 10.1016/j.brainres.2005.02.006.PubMedCrossRefGoogle Scholar
  9. Bandopadhyay, R., Kingsbury, A. E., Cookson, M. R., et al. (2004). The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain, 127, 420–430. doi: 10.1093/brain/awh054.PubMedCrossRefGoogle Scholar
  10. Barber, S. C., Mead, R. J., & Shaw, P. J. (2006). Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochimica et Biophysica Acta, 1762, 1051–1067.PubMedGoogle Scholar
  11. Beal, M. F., Ferrante, R. J., Browne, S. E., Mathews, R. T., Kowall, N. W., & Brown Jr., R. H. (1997). Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Annals of Neurology, 42, 644–654. doi: 10.1002/ana.410420416.PubMedCrossRefGoogle Scholar
  12. Bogdanov, M., Brown, R. H., Matson, W., et al. (2000). Increased oxidative damage to DNA in ALS patients. Free Radical Biology & Medicine, 29, 652–658. doi: 10.1016/S0891-5849(00)00349-X.CrossRefGoogle Scholar
  13. Bonifati, V., Rizzu, P., van Baren, M. J., et al. (2003). Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 299, 256–259. doi: 10.1126/science.1077209.PubMedCrossRefGoogle Scholar
  14. Canet-Aviles, R. M., Wilson, M. A., Miller, D. W., et al. (2004). The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proceedings of the National Academy of Sciences of the United States of America, 101, 9103–9108. doi: 10.1073/pnas.0402959101.PubMedCrossRefGoogle Scholar
  15. Carri, M. T., Ferri, A., Cozzolino, M., Calabrese, L., & Rotilio, G. (2003). Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Research Bulletin, 61, 365–374. doi: 10.1016/S0361-9230(03)00179-5.PubMedCrossRefGoogle Scholar
  16. Casoni, F., Basso, M., Massignan, T., et al. (2005). Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis. The Journal of Biological Chemistry, 280, 16295–16304. doi: 10.1074/jbc.M413111200.PubMedCrossRefGoogle Scholar
  17. Cha, C. I., Chung, Y. H., Shin, C. M., et al. (2000). Immunochemical study on the distribution of nitrotyrosine in the brain of the transgenic mice expressing a human Cu/Zn SOD mutation. Brain Research, 853, 156–161. doi: 10.1016/S0006-8993(99)02302-1.PubMedCrossRefGoogle Scholar
  18. Choi, J., Sullards, M. C., Olzmann, J. A., et al. (2006). Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. The Journal of Biological Chemistry, 281, 10816–10824. doi: 10.1074/jbc.M509079200.PubMedCrossRefGoogle Scholar
  19. Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P. (2006). DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proceedings of the National Academy of Sciences of the United States of America, 103, 15091–15096. doi: 10.1073/pnas.0607260103.PubMedCrossRefGoogle Scholar
  20. Ferrante, R. J., Browne, S. E., Shinobu, L. A., et al. (1997a). Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. Journal of Neurochemistry, 69, 2064–2074.PubMedCrossRefGoogle Scholar
  21. Ferrante, R. J., Shinobu, L. A., Schulz, J. B., et al. (1997b). Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. Annals of Neurology, 42, 326–334. doi: 10.1002/ana.410420309.PubMedCrossRefGoogle Scholar
  22. Fitzmaurice, P. S., Shaw, I. C., Kleiner, H. E., et al. (1996). Evidence for DNA damage in amyotrophic lateral sclerosis. Muscle & Nerve, 19, 797–798.Google Scholar
  23. Gurney, M. E., Pu, H., Chiu, A. Y., et al. (1994). Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science, 264, 1772–1775. doi: 10.1126/science.8209258.PubMedCrossRefGoogle Scholar
  24. Hall, E. D., Andrus, P. K., Oostveen, J. A., Fleck, T. J., & Gurney, M. E. (1998). Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS. Journal of Neuroscience Research, 53, 66–77. doi: 10.1002/(SICI)1097-4547(19980701)53:1<66::AID-JNR7>3.0.CO;2-H.PubMedCrossRefGoogle Scholar
  25. Harraz, M. M., Marden, J. J., Zhou, W., et al. (2008). SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. The Journal of Clinical Investigation, 118, 659–670.PubMedGoogle Scholar
  26. Hensley, K., Fedynyshyn, J., Ferrel, S., et al. (2003). Message and protein level elevations of tumor necrosis factor alpha and TNF-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. Neurobiology of Disease, 14, 74–80. doi: 10.1016/S0969-9961(03)00087-1.PubMedCrossRefGoogle Scholar
  27. Hensley, K., Mhatre, M., Mou, S., et al. (2006). On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. Antioxidants & Redox Signalling, 8, 2075–2087. doi: 10.1089/ars.2006.8.2075.CrossRefGoogle Scholar
  28. Ihara, Y., Nobukuni, K., Takata, H., & Hayabara, T. (2005). Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu,Zn-superoxide dismutase mutation. Neurological Research, 27, 105–108. doi: 10.1179/016164105X18430.PubMedCrossRefGoogle Scholar
  29. Ilieva, E. V., Ayala, V., Jove, M., et al. (2007). Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain, 130, 3111–3123. doi: 10.1093/brain/awm190.PubMedCrossRefGoogle Scholar
  30. Jokic, N., Di Scala, F., Dupuis, L., et al. (2003). Early activation of antioxidant mechanisms in muscle of mutant Cu/Zn-superoxide dismutase-linked amyotrophic lateral sclerosis mice. Annals of the New York Academy of Sciences, 1010, 552–556. doi: 10.1196/annals.1299.102.PubMedCrossRefGoogle Scholar
  31. Kim, R. H., Smith, P. D., Aleyasin, H., et al. (2005). Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proceedings of the National Academy of Sciences of the United States of America, 102, 5215–5220. doi: 10.1073/pnas.0501282102.PubMedCrossRefGoogle Scholar
  32. Kraft, A. D., Resch, J. M., Johnson, D. A., & Johnson, J. A. (2007). Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1. Experimental Neurology, 207, 107–117. doi: 10.1016/j.expneurol.2007.05.026.PubMedCrossRefGoogle Scholar
  33. Lev, N., Ickowicz, D., Melamed, E., & Offen, D. (2008). Oxidative insults induce DJ-1 upregulation and redistribution: implications for neuroprotection. Neurotoxicology, 29, 397–405. doi: 10.1016/j.neuro.2008.01.007.PubMedCrossRefGoogle Scholar
  34. Liu, R., Althaus, J. S., Ellerbrock, B. R., Becker, D. A., & Gurney, M. E. (1998). Enhanced oxygen radical production in a transgenic mouse model of familial amyotrophic lateral sclerosis. Annals of Neurology, 44, 763–770. doi: 10.1002/ana.410440510.PubMedCrossRefGoogle Scholar
  35. Liu, J., Lillo, C., Jonsson, P. A., et al. (2004). Toxicity of familial ALS-Linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron, 43, 5–17. doi: 10.1016/j.neuron.2004.06.016.PubMedCrossRefGoogle Scholar
  36. Liu, D., Wen, J., Liu, J., & Li, L. (1999). The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. The FASEB Journal, 13, 2318–2328.PubMedGoogle Scholar
  37. Mahoney, D. J., Kaczor, J. J., Bourgeois, J., Yasuda, N., & Tarnopolsky, M. A. (2006). Oxidative stress and antioxidant enzyme upregulation in SOD1-G93A mouse skeletal muscle. Muscle & Nerve, 33, 809–816. doi: 10.1002/mus.20542.CrossRefGoogle Scholar
  38. Martinat, C., Shendelman, S., Jonason, A., et al. (2004). Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES-derived cell model of primary Parkinsonism. PLoS Biology, 2, e327. doi: 10.1371/journal.pbio.0020327.PubMedCrossRefGoogle Scholar
  39. Menzies, F. M., Yenisetti, S. C., & Min, K. T. (2005). Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Current Biology, 15, 1578–1582. doi: 10.1016/j.cub.2005.07.036.PubMedCrossRefGoogle Scholar
  40. Meulener, M., Whitworth, A. J., Armstrong-Gold, C. E., et al. (2005). Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease. Current Biology, 15, 1572–1577. doi: 10.1016/j.cub.2005.07.064.PubMedCrossRefGoogle Scholar
  41. Mitsumoto, A., Nakagawa, Y., Takeuchi, A., Okawa, K., Iwamatsu, A., & Takanezawa, Y. (2001). Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat. Free Radical Research, 35, 301–310. doi: 10.1080/10715760100300831.PubMedCrossRefGoogle Scholar
  42. Nagakubo, D., Taira, T., Kitaura, H., et al. (1997). DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochemical and Biophysical Research Communications, 231, 509–513. doi: 10.1006/bbrc.1997.6132.PubMedCrossRefGoogle Scholar
  43. Perluigi, M., Poon, H. F., Hensley, K., et al. (2005). Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice: a model of familial amyotrophic lateral sclerosis. Free Radical Biology & Medicine, 38, 960–968. doi: 10.1016/j.freeradbiomed.2004.12.021.CrossRefGoogle Scholar
  44. Poon, H. F., Hensley, K., Thongboonkerd, V., et al. (2005). Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateral sclerosis. Free Radical Biology & Medicine, 39, 453–462. doi: 10.1016/j.freeradbiomed.2005.03.030.CrossRefGoogle Scholar
  45. Sekito, A., Koide-Yoshida, S., Niki, T., Taira, T., Iguchi-Ariga, S. M., & Ariga, H. (2006). DJ-1 interacts with HIPK1 and affects H2O2-induced cell death. Free Radical Research, 40, 155–165. doi: 10.1080/10715760500456847.PubMedCrossRefGoogle Scholar
  46. Shaw, P. J., Ince, P. G., Falkous, G., & Mantle, D. (1995). Oxidative damage to protein in sporadic motor neuron disease spinal cord. Annals of Neurology, 38, 691–695. doi: 10.1002/ana.410380424.PubMedCrossRefGoogle Scholar
  47. Shibata, N., Kawaguchi, M., Uchida, K., et al. (2007). Protein-bound crotonaldehyde accumulates in the spinal cord of superoxide dismutase-1 mutation-associated familial amyotrophic lateral sclerosis and its transgenic mouse model. Neuropathology, 27, 49–61. doi: 10.1111/j.1440-1789.2006.00746.x.PubMedCrossRefGoogle Scholar
  48. Shibata, N., Nagai, R., Uchida, K., et al. (2001). Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Research, 917, 97–104. doi: 10.1016/S0006-8993(01)02926-2.PubMedCrossRefGoogle Scholar
  49. Simpson, E. P., Henry, Y. K., Henkel, J. S., Smith, R., & Appel, S. H. (2004). Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology, 62, 1758–1765.PubMedGoogle Scholar
  50. Smith, R. G., Henry, Y. K., Mattson, M. P., & Appel, S. H. (1998). Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Annals of Neurology, 44, 696–699. doi: 10.1002/ana.410440419.PubMedCrossRefGoogle Scholar
  51. Taira, T., Saito, Y., Niki, T., Iguchi-Ariga, S. M., Takahashi, K., & Ariga, H. (2004). DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Reports, 5, 213–218. doi: 10.1038/sj.embor.7400074.PubMedCrossRefGoogle Scholar
  52. Tohgi, H., Abe, T., Yamazaki, K., Murata, T., Ishizaki, E., & Isobe, C. (1999). Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis. Annals of Neurology, 46, 129–131. doi: 10.1002/1531-8249(199907)46:1<129::AID-ANA21>3.0.CO;2-Y.PubMedCrossRefGoogle Scholar
  53. Yokota, T., Sugawara, K., Ito, K., Takahashi, R., Ariga, H., & Mizusawa, H. (2003). Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochemical and Biophysical Research Communications, 312, 1342–1348. doi: 10.1016/j.bbrc.2003.11.056.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  • Nirit Lev
    • 1
  • Debby Ickowicz
    • 1
  • Yael Barhum
    • 1
  • Eldad Melamed
    • 1
  • Daniel Offen
    • 1
  1. 1.Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center-Beilinson Campus, The Sackler School of MedicineTel Aviv UniversityPetah TikvaIsrael

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