Skip to main content

Advertisement

Log in

Spinal Cord mRNA Profile in Patients with ALS: Comparison with Transgenic Mice Expressing the Human SOD-1 Mutant

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons in the cerebral cortex, brain stem, and spinal cord. Most cases (90%) are classified as sporadic ALS (sALS). The remainder 10% are inherited and referred to as familial ALS, and 2% of instances are due to mutations in Cu/Zn superoxide dismutase (SOD1). Using cDNA microarray on postmortem spinal cord specimens of four sALS patients compared to four age-matched nonneurological controls, we found major changes in the expression of mRNA in 60 genes including increase of cathepsin B and cathepsin D (by the factors 2 and 2.3, respectively), apolipoprotein E (Apo E; factor 4.2), epidermal growth factor receptor (factor 10), ferritin (factor 2), and lysosomal trafficking regulator (factor 10). The increase in the expression of these genes was verified by quantitative reverse transcriptase polymerase chain reaction. Further analysis of these genes in hSOD1-G93A transgenic mice revealed increase in the expression in parallel with the deterioration of motor functions quantified by means of rotorod performance. The comparability of the findings in sALS patients and in the hSOD1-G93A transgenic mouse model suggests that the examined genes may play a specific role in the pathogenesis of ALS.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Bendotti, C., Tortarolo, M., Suchak, S. K., Calvaresi, N., Carvelli, L., Bastone, A., et al. (2001). Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. Journal of Neurochemistry, 7(4), 737–746.

    Article  Google Scholar 

  • Birecree, E., Whetsell, W. O. Jr., Stoscheck, C., King, L. E. Jr., & Nanney, L. B. (1988). Immunoreactive epidermal growth factor receptors in neuritic plaques from patients with Alzheimer’s disease. Journal of Neuropathology and Experimental Neurology, 47(5), 549–560.

    Article  PubMed  CAS  Google Scholar 

  • Bruijn, L. I., Miller, T. M., & Cleveland, D. W. (2004). Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annual Review of Neuroscience, 27, 723–749.

    Article  PubMed  CAS  Google Scholar 

  • Callahan, L. M., Vaules, W. A., & Coleman, P. D. (1999). Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. Journal of Neuropathology and Experimental Neurology, 58(3), 275–287.

    Article  PubMed  CAS  Google Scholar 

  • Certain, S., Barrat, F., Pastural, E., Le Deist, F., Goyo-Rivas, J., Jabado, N., et al. (2000). Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak–Higashi syndrome. Blood, 95(3), 979–983.

    PubMed  CAS  Google Scholar 

  • Cudkowicz, M. E., McKenna-Yasek, D., Sapp, P. E., Chin, W., Geller, B., Hayden, D. L., et al. (1997) Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Annals of Neurology, 49(1), 213–222.

    CAS  Google Scholar 

  • Drory, V. E., Birnbaum, M., Korczyn, A. D., & Chapman, J. (2001). Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis. Journal of the Neurological Sciences, 190(1–2), 17–20.

    Article  PubMed  CAS  Google Scholar 

  • Embacher, N., Kaufmann, W. A., Beer, R., Maier, H., Jellinger, K. A., Poewe, W., et al. (2001). Apoptosis signals in sporadic amyotrophic lateral sclerosis: an immunocytochemical study. Acta Neuropathologica, 102(5), 426–434.

    PubMed  CAS  Google Scholar 

  • Erschbamer, M., Pernold, K., & Olson, L. (2007) Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. Journal of Neuroscience, 27(24), 6428–6435.

    Article  PubMed  CAS  Google Scholar 

  • Ferrante, R. J., Browne, S. E., Shinobu, L. A., Bowling, A. C., Baik, M. J., MacGarvey, U., et al. (1997). Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. Journal of Neurochemistry, 69(5), 2064–2074.

    PubMed  CAS  Google Scholar 

  • Ferri, A., Nencini, M., Battistini, S., Giannini, F., Siciliano, G., Casali, C., et al. (2004). Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosis patients. Journal of Neurochemistry, 90, 1237–1242.

    Article  PubMed  CAS  Google Scholar 

  • Foghsgaard, L., Wissing, D., Mauch, D., Lademann, U., Bastholm, L., Boes, M., et al. (2001). Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. Journal of Cell Biology, 153(5), 999–1010.

    Article  PubMed  CAS  Google Scholar 

  • Gros-Louis, F., Gaspar, C., & Rouleau, G. A. (2006). Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochimica et Biophysica Acta, 1762(11–12), 956–972.

    PubMed  CAS  Google Scholar 

  • Guegan, C., & Przedborski, S. (2003). Programmed cell death in amyotrophic lateral sclerosis. Journal of Clinical Investigation, 111(2), 153–161.

    PubMed  CAS  Google Scholar 

  • Guégan, C., Vila, M., Rosoklija, G., Hays, A. P., & Przedborski, S. (2001). Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. Journal of Neuroscience, 21(17), 6569–6576.

    PubMed  Google Scholar 

  • Gurney, M. E., Cutting, F. B., Zhai, P., Doble, A., Taylor, C. P., Andrus, P. K., et al. (1996). Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Annals of Neurology, 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., 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 

  • Haasdijk, E. D., Vlug, A., Mulder, M. T., & Jaarsma, D. (2002). Increased apolipoprotein E expression correlates with the onset of neuronal degeneration in the spinal cord of G93A-SOD1 mice. Neuroscience Letters, 335(1), 29–33.

    Article  PubMed  CAS  Google Scholar 

  • Howland, D. S., Liu, J., She, Y., Goad, B., Maragakis, N. J., Kim, B., et al. (2002). Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proceedings of the National Academy of Sciences of the United States of America, 99, 1604–1609.

    Article  PubMed  CAS  Google Scholar 

  • Hoyaux, D., Boom, A., Van den Bosch, L., Belot, N., Martin. J. J., Heizmann, C. W., et al. (2002). S100A6 overexpression within astrocytes associated with impaired axons from both ALS mouse model and human patients. Journal of Neuropathology and Experimental Neurology, 61(8), 736–744.

    PubMed  CAS  Google Scholar 

  • Jacobsson, J., Jonsson, P. A., Andersen, P. M., Forsgren, L., & Marklund, S. L. (2001). Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations. Brain, 124, 1461–1466.

    Article  PubMed  CAS  Google Scholar 

  • Kagedal, K., Johansson, U., & Ollinger, K. (2000). The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress. FASEB Journal, 15(9), 1592–1594.

    Google Scholar 

  • Kajiwara, Y., Yamasaki, F., Hama, S., Yahara, K., Yoshioka, H., Sugiyama, K., et al. (2003). Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer, 97(4), 1077–1083.

    Article  PubMed  Google Scholar 

  • Kikuchi, H., Yamada, T., Furuya, H., Doh-ura, K., Ohyagi, Y., Iwaki, T., et al. (2003). Involvement of cathepsin B in the motor neuron degeneration of amyotrophic lateral sclerosis. Acta Neuropathologica, 105(5), 462–468.

    PubMed  CAS  Google Scholar 

  • Kingham, P. J., & Pocock, J. M. (2001). Microglial secreted cathepsin B induces neuronal apoptosis. Journal of Neurochemistry, 76(5), 1475–1484.

    Article  PubMed  CAS  Google Scholar 

  • Kohda, Y., Yamashima, T., Sakuda, K., Yamashita, J., Ueno, T., Kominami, E., et al. (1996). Dynamic changes of cathepsins B and L expression in the monkey hippocampus after transient ischemia. Biochemical and Biophysical Research Communications, 228(2), 616–622.

    Article  PubMed  CAS  Google Scholar 

  • Kornblum, H. I., Hussain, R., Wiesen, J., Miettinen, P., Zurcher, S. D., Chow, K., et al. (1998). Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor. Journal of Neuroscience Research, 53(6), 697–717.

    Article  PubMed  CAS  Google Scholar 

  • Lacomblez, L., Doppler, V., Beucler, I., Costes, G., Salachas, F., Raisonnier, A., et al. (2002). APOE: a potential marker of disease progression in ALS. Neurology, 58(7), 1112–1114.

    PubMed  CAS  Google Scholar 

  • Li, M., Ona, V. O., Guegan, C., Kaul, M., Tenneti, L., Zhang, X., et al. (2000). Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science, 288(5464), 335–339.

    Article  PubMed  CAS  Google Scholar 

  • Liu, D. (1996). The roles of free radicals in amyotrophic lateral sclerosis. Journal of Molecular Neuroscience, 7(3), 159–167.

    Article  PubMed  CAS  Google Scholar 

  • Liu, B., Chen, H., Johns, T. G., & Neufeld, A. H. (2006). Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. Journal of Neuroscience, 26(28), 7532–7540.

    Article  PubMed  CAS  Google Scholar 

  • Liu, B., & Neufeld, A. H. (2007). Activation of epidermal growth factor receptors in astrocytes: From development to neural injury. Journal of Neuroscience Research, 85(16), 3523–3529.

    Article  PubMed  CAS  Google Scholar 

  • Malaspina, A., Kaushik, N., & de Belleroche, J. (2001). Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. Journal of Neurochemistry, 77(1), 132–145.

    PubMed  CAS  Google Scholar 

  • Martin, L. J. (1999). Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. Journal of Neuropathology and Experimental Neurology, 58(5), 459–471.

    Article  PubMed  CAS  Google Scholar 

  • Masliah, E., Mallory, M., Veinbergs, I., Miller, A., & Samuel, W. (1996). Alterations in apolipoprotein E expression during aging and neurodegeneration. Progress in Neurobiology, 50, 493–503.

    Article  PubMed  CAS  Google Scholar 

  • McGeer, P. L., & McGeer, E. G. (2002). Inflammatory processes in amyotrophic lateral sclerosis. Muscle & Nerve, 26(4), 459–470.

    Article  CAS  Google Scholar 

  • Menzies, F. M., Grierson, A. J., Cookson, M. R., Heath, P. R., Tomkins, J., Figlewicz, D. A., et al. (2002). Selective loss of neurofilament expression in Cu/Zn superoxide dismutase (SOD1) linked amyotrophic lateral sclerosis. Journal of Neurochemistry, 82(5), 1118–1128.

    Article  PubMed  CAS  Google Scholar 

  • Mizuno, Y., Amari, M., Takatama, M., Aizawa, H., Mihara, B., & Okamoto, K. (2006). Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathologica, 112, 597–603.

    Article  PubMed  CAS  Google Scholar 

  • Moulard, B., Sefiani, A., Laamri, A., Malafosse, A., & Camu, W. (1996). Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis. Journal of the Neurological Sciences, 139, 34–37 (Suppl).

    Google Scholar 

  • Mu, X., He, J., Anderson, D. W., Trojanowski, J. Q., & Springer, J. E. (1996). Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. Annals of Neurology, 40(3), 379–386.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura, Y., Takeda, M., Suzuki, H., Hattori, H., Tada, K., Hariguchi, S., et al. (1991). Abnormal distribution of cathepsins in the brain of patients with Alzheimer’s disease. Neuroscience Letters, 130(2), 195–198.

    Article  PubMed  CAS  Google Scholar 

  • Nakanishi, H., Amano, T., Sastradipura, D. F., Yoshimine, Y., Tsukuba, T., Tanabe, K., et al. (1997). Increased expression of cathepsins E and D in neurons of the aged rat brain and their colocalization with lipofuscin and carboxy-terminal fragments of Alzheimer amyloid precursor protein. Journal of Neurochemistry, 68(2), 739–749.

    Article  PubMed  CAS  Google Scholar 

  • Olsen, M. K., Roberds, S. L., Ellerbrock, B. R., Fleck, T. J., McKinley, D. K., & Gurney, M. E. (2001). Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. Annals of Neurology, 50(6), 730–740.

    Article  PubMed  CAS  Google Scholar 

  • Papassotiropoulos, A., Lewis, H. D., Bagli, M., Jessen, F., Ptok, U., Schulte, A., et al. (2002). Cerebrospinal fluid levels of beta-amyloid(42) in patients with Alzheimer’s disease are related to the exon 2 polymorphism of the cathepsin D gene. Neuroreport, 13(10), 1291–1294.

    Article  PubMed  CAS  Google Scholar 

  • Pasinelli, P., & Brown, R. H. (2006). Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nature Reviews Neuroscience, 7(9), 710–723 (review).

    Article  PubMed  CAS  Google Scholar 

  • Pasinelli, P., Houseweart, M. K., Brown, R. H., & Cleveland, D. W. (2000). Caspase 1 and 3 are sequentially activated in motor neuron death in Cu, Zn superoxide dismutase-mediated familial amyotorophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 97, 13901–13906.

    Article  PubMed  CAS  Google Scholar 

  • Pedersen, W. A., Fu, W., Keller, J. N., Markesbery, W. R., Appel, S., Smith, R. G., et al. (1998). Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Annals of Neurology, 44(5), 819–824.

    Article  PubMed  CAS  Google Scholar 

  • Pedersen, W. A., Luo, H., Kruman, I., Kasarskis, E., & Mattson, M. P. (2000). The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis. FASEB Journal, 14(7), 913–924.

    PubMed  CAS  Google Scholar 

  • Rothstein, J. D., Martin, L. J., & Kuncl, R. W. (1992). Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. New England Journal of Medicine, 326(22), 1464–1468.

    PubMed  CAS  Google Scholar 

  • Sibilia, M., Steinbach, J. P., Stingl, L., Aguzzi, A., & Wagner, E. F. (1998). A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor. EMBO Journal, 17(3), 719–731.

    Article  PubMed  CAS  Google Scholar 

  • Simmons, D. A., Casale, M., Alcon, B., Pham, N., Narayan, N., & Lynch, G. (2007). Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia(Galaţi), 55(10), 1074–1084.

    Google Scholar 

  • Takuma, K., Kiriu, M., Mori, K., Lee, E., Enomoto, R., Baba, A., et al. (2003). Roles of cathepsins in reperfusion-induced apoptosis in cultured astrocytes. Neurochemistry International, 42(2), 153–159.

    Article  PubMed  CAS  Google Scholar 

  • Threadgill, D. W., Dlugosz, A. A., Hansen, L. A., Tennenbaum, T., Lichti, U., Yee, D., et al. (1995). Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science, 269(5221), 230–234.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The project was partially supported by the National Parkinson Foundation, Miami, FL, USA; the Norma and Alan Aufzein Chair for Research in Parkinson’s disease, Tel Aviv University, Israel; and the Scientific and Technical Cooperation Austria–Israel, project #III/7 1999.

We are very grateful to Prof. Dr. Manfred Gerlach, Department of Clinical Neurochemistry, Medical Faculty, Würzburg, Germany, for providing us with spinal cord tissue of a patient who died from sALS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel Offen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Offen, D., Barhum, Y., Melamed, E. et al. Spinal Cord mRNA Profile in Patients with ALS: Comparison with Transgenic Mice Expressing the Human SOD-1 Mutant. J Mol Neurosci 38, 85–93 (2009). https://doi.org/10.1007/s12031-007-9004-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-007-9004-z

Keywords

Navigation