Skip to main content
SpringerLink
Log in

Mechanism of Myelin Breakdown in Experimental Demyelination: A Putative Role for Calpain

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Although calpain has been extensively studied, its physiological function is poorly understood. In contrast, its role in the pathophysiology of various diseases has been implicated, including that of experimental allergic encephalomyelitis (EAE), an animal model of the demyelinating disease multiple sclerosis (MS). In EAE, calpain degrades myelin proteins, including myelin basic protein (MBP), suggesting a role for calpain in the breakdown of myelin in this disease. Subsequent studies revealed increased calpain activity and expression in the glial and inflammatory cells concomitant with loss of axon and myelin proteins. This suggested a crucial role for calpain in demyelinating diseases.

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

REFERENCES

  1. Hallpike, J. B. and Adams, C. W. M. 1969. Proteolysis of myelin breakdown: a review of recent histochemical and biochemical studies. Histochem. J. 1:559–578.

    Google Scholar 

  2. Cross, A. H., Dolich, S., and Raine, C. S. 1990. Antigen processing of myelin basic protein is required to recognition by T-cells inducing EAE. Cell Immunol. 129:22–031.

    Google Scholar 

  3. Brostoff, S. W., Reuter, W., Hichens, M., and Eylar, E. H. 1974. Specific cleavage of the A1 protein from myelin with cathepsin D. J. Biol. Chem. 249:559–567.

    Google Scholar 

  4. Allen, I. 1983. Hydrolytic enzymes in multiple sclerosis. Pages 1–17, in Zimmerman, H. M., (ed.), Progress in Neuropathology, Vol. 5, Raven Press, New York.

    Google Scholar 

  5. Smith, M. E. 1977. The role of proteolytic enzymes in experimental allergic encephalomyelitis. Neurochem. Res. 2:223–246.

    Google Scholar 

  6. Hashim, G. A., Day, E. D., Fredane, L., Intitola, P., and Carvalho, E. 1986. Biological activity of regions 65–102 of the myelin basic protein. J. Neurosci. Res. 16:467–478.

    Google Scholar 

  7. Banik, N. L., McAlhaney, W. W., and Hogan, E. L. 1985. Calcium-stimulated proteolysis in myelin: Evidence for a Ca21-activated neutral proteinase associated with purified myelin of rat CNS. J. Neurochem. 45:581–588.

    Google Scholar 

  8. Banik, N. L., Chou, S., Diebler, G. E., Krutzch, H., and Hogan, E. L. 1994. Peptide bond specificity of calpain: Proteolysis of human myelin basic protein (HMBP). J. Neurosci. Res. 37:489–496.

    Google Scholar 

  9. Yanagisawa, K., Sato, S., O'shannessy, D. J., Quarles, R. K., Suzuki, K., and Miyatake, T. 1988. Myelin-associated calpain II. J. Neurochem. 51:803–807.

    Google Scholar 

  10. Kolehmainen, E. and Kaisto, T. 1989. Degradation of exogenous MBP by myelin Ca2+-activated neutral protease and effect of extraction on myelin on enzyme activity. Neurochem. Int. 14:11–15.

    Google Scholar 

  11. Sato, S., Quarles, R. H., Brady, R. O., and Tourtellotte, W. W. 1984. Elevated neutral proteinase activity in myelin from multiple sclerosis brain. Ann. Neurol. 15:264–267.

    Google Scholar 

  12. Inuzuka, T., Sato, S., Baba, H., and Miyatake, T. 1987. Degradation of myelin basic protein in myelin by cerebrospinal fluid and effect of protease inhibitors. Pages 489–523, in: Lowenthal, A. N., and Raus, J., (ed.), Cellular and Humoral Components of Cerebrospinal Fluid in Multiple Sclerosis, Vol. 129, Plenum Press, New York.

    Google Scholar 

  13. Berlet, H. H. 1987. Calcium dependent neutral protease activity of myelin from bovine spinal cord: evidence for soluble cleavage products of myelin proteins. Neurosci. Lett. 73:266–270.

    Google Scholar 

  14. Tsubata, T. and Takahashi, K. 1989. Limited proteolysis of bovine myelin basic protein by calcium-dependent proteinase from bovine spinal cord. J. Biochem. 105:23–28.

    Google Scholar 

  15. Guroff, G. 1964. A neutral calcium-activated proteinase from the soluble fraction of rat brain. J. Biol. Chem. 239:149–155.

    Google Scholar 

  16. Shearer, T. R. and David, L. L. 1990. Calpain in lens and cataract. Pages 265–274, in Mellgren, R. L., and Murachi, T., (eds.), Intracellular Calcium-Dependent Proteolysis, CRC Press, Boca Raton.

    Google Scholar 

  17. Suzuki, K., Sorimachi, H., Yoshizawa, T., Kinbara, K., and Ishiura, S. 1995. Calpain: novel family members, activation, and physiological function. Biol. Chem. 376:523–529.

    Google Scholar 

  18. Murachi, T. 1984. Calcium-dependent proteinases and specific inhibitors: Calpain and calpastatin. Biochem. Soc. Symp. 49:149–167.

    Google Scholar 

  19. Suzuki, K. 1987. Domain structure and activity regulation. Trends Biochem. Sci. 12:103–105.

    Google Scholar 

  20. Saido, T. C., Shibata M., Takenawa, T., Murofushi, H., and Suzuki K. 1992. Positive regulation of μ-calpain action by polyphosphoinositides. J. Biol. Chem. 267:24585–24590.

    Google Scholar 

  21. Dayton, W. R., Reville, W. J., Goll, D. E., and Stromer, M. H. 1976. A Ca2+ activated protease possibly involved in myofibrillar turnover. Biochemistry 15:2159–2167.

    Google Scholar 

  22. Nelson, W. J. and Traub, P. 1982. Purification and further characterization of the Ca2+-activated neutral proteinase specific for the intermediate filament proteins, vimentin and desmin. J. Biol. Chem. 257:5544–5553.

    Google Scholar 

  23. Sakai, K., Akauma, H., Imahori, K., and Kawashima, S. 1987. A unique specificity of a calcium activated neutral protease indicated in histone hydrolysis. J. Biochem. 101:911–918.

    Google Scholar 

  24. Schlaepfer, W. W. and Zimmerman, U. J. P. 1990. The degradation of neurofilaments by calpains. Pages 241–250, in Mellgren, R. L., and Murachi, T. (eds.), Intracellular Calcium-Dependent Proteolysis, CRC Press, Boca Ratons.

    Google Scholar 

  25. Banik, N. L., Chakrabarti, A. K., and Hogan, E. L. 1992. Calcium-Activated Neutral Proteinase in Myelin: Its Role and Function. Pages 571–598, in: Martenson, R. (ed.), Myelin, Biology and Chemistry. CRC Press, Boca Raton.

    Google Scholar 

  26. Iwamoto, N., Thangnipon, W., Crawford, C., and Emson, P. C. 1991. Localization of calpain immunoreactivity in senile plaques and in neurons undergoing neurofibrillary degeneration in Alzheimer's disease. Brain Res. 561:177–180.

    Google Scholar 

  27. Honda, T., Hamos, J., and Nixon, R. A. 1992. Soluble derivative of APP: A potential relationship to abnormal calpain activation in Alzheimer brain. Soc. Neurosci. 18:733.

    Google Scholar 

  28. Bartus, R. L., Baker, K. L., Heiser, A. D., Sawyer, S. D., Dean, R. L., Elliott, P. J., and Straub, J. A. 1994. Post-ischemic administration of AK-295, a calpain inhibitor provides substantial protection against focal ischemic brain damage. J. Cereb. Blood Flow Metab. 14:537–544.

    Google Scholar 

  29. Rabbani, N., Moses, L., and Anandaraj, M. P. 1987. Calcium activated neutral proteinase and its endogenous inhibitor in tissue of dystrophic and normal mice. Biochem. Med. Metab. Biol. 37:282–286.

    Google Scholar 

  30. Kar, N. C. and Pearson, C. M. 1978. Muscular dystrophy and activation of proteinase. Muscle and Nerve 1:308–313.

    Google Scholar 

  31. Shields, D. C. and Banik, N. L. 1999. Pathophysiological role of calpain in experimental demyelination. J. Neurosci. Res. 55:533–541.

    Google Scholar 

  32. Shields, D. C. and Banik, N. L. 1998. Putative role of calpain in the pathophysiology of experimental optic neuritis. Exp. Eye Res. 67:403–410.

    Google Scholar 

  33. Newcombe, J., Glynn, P., and Cuzner, M. L. 1982. The immunological identification of brain proteins on cellulose nitrate in human demyelinating disease. J. Neurochem. 38:267–374.

    Google Scholar 

  34. Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudnick, R., Mork, S., and Bo, L. 1998. Axonal Transection in the lesions of multiple sclerosis. NEJM 338:278–285.

    Google Scholar 

  35. Moller, J. R. 1996. Rapid conversion of myelin-associated glycoprotein to a soluble derivative in primates. Brain Res. 741:27–31.

    Google Scholar 

  36. Shields, D. and Banik, N. L. 1998. Upregulation of calpain activity and expression in experimental allergic encephalomyelitis (EAE): A putative role for calpain in demyelination. Brain Res. 794:68–74.

    Google Scholar 

  37. Schaecher, K. E., Dinkins, J., Matzelle, D., and Banik, N. L. 2001. FASEB Meeting.

  38. Shields, D. C., Schaecher, K. E., Goust, J. M., and Banik, N. L. 1999. Calpain activity and expression are increased in the splenic inflammatory cells associated with experimental allergic encephalomyelitis. J. Neuroimmunol. 99:1–12.

    Google Scholar 

  39. Yano, T., Kobayashi, A., Kurata, S., and Natori, S. 1997. Purification and characterization of cathepsin B mRNA 3′-untranslated-region-binding protein (CBBP), a protein that represses cathepsin B mRNA translation. Eur. J. Biochem. 245:260–265.

    Google Scholar 

  40. Smith, M. E., Vandermaesen, K., Somera, F., and Sobel, R. 1998. Effects of phorbol myristate acetate (PMA) on functions of macrophages and microglia in vitro. Neurochem. Res. 23:427–434.

    Google Scholar 

  41. Deshpande, R. V., Goust, J. M., Hogan, E. L., and Banik, E. L. 1995. Calpain secreted from activated lymphoid cells degrades myelin. J. Neurosci. Res. 42:259–265.

    Google Scholar 

  42. Ray, S. K., Schaecher, K., Shields, D. C., Hogan, E. L., and Banik, N. L. 2000. Combined TUNEL and double immunofluorescence labeling for detecting apoptotic mononuclear phagocytes in autoimmune demyelinating disease. Brain Res. Protocol 5:305–311.

    Google Scholar 

  43. Algarte, M., Lecine, P., Costeelo, R., Plet, A., Olive, D., and Imbert, J. 1995. In vivo regulation of interleukin-2 receptor-a transcription by the coordinated binding of constitutive and inducible factors in human primary T cells. EMBO J. 14:5060–5072.

    Google Scholar 

  44. Owens, T., Tran, E., Hassan-Zahraee M., and Krakowski M. 1998. Immune cell entry to the CNS-a focus for immunoregulation of EAE. Res. Immunol. 149:781–789.

    Google Scholar 

  45. Clementi, E., Martino, G., Grimaldi, L. M. E., Brambilla, E., and Meldolesi, J. 1994. Intracellular Ca2+ stores of T lymphocytes: changes induced by in vitro and in vivo activation. Euro. J. Immunol. 24:1365–1371.

    Google Scholar 

  46. Silberberg, D. H., Manning, M. C., and Schreiber, A. D. 1984. Tissue culture demyelination by normal human serum. Ann. Neurol. 15:575–580.

    Google Scholar 

  47. Linnington, C. and Lassmann, H. 1987. Antibody responses in chronic relapsing experimental allergic encephalomyelitis: correlation of serum demyelinating activity with antibody titre to the myelin/oligodendrocyte glycoprotein (MOG). J. Neuroimmunol. 17:61–69.

    Google Scholar 

  48. Zajicek, J. P., Wing, M., Scolding, N. J., and Compston, D. A. 1992. Interactions between oligodendrocytes and microglia. A major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain 115:1611–1631.

    Google Scholar 

  49. Ozawa, K., Saida, T., Saida, K., Nishitani, H., and Kameyama, M. 1989. In vivo CNS demyelination mediated by anti-galactocerebroside antibody. Acta Neuropathol. (Berlin) 77:621–628.

    Google Scholar 

  50. Scolding, N. J., Jones, J., Compston, D. A., and Morgan, B. P. 1990. Oligodendrocyte susceptibility to injury by T-cell perforin. Immunology 70:6–10.

    Google Scholar 

  51. Shields, D. C., Schaecher, K. E., Saido, T. C., and Banik, N. L. 1999. A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. Proc. Natl. Acad. Sci. 96:11486–11491.

    Google Scholar 

  52. Deshpande, R. V., Goust, J. M., Chakrabarti, A. K., Barbosa, E., Hogan, E. L., and Banik, N. L. 1995. Calpain expression in lymphoid cells. J. Biol. Chem. 270:2497–2505.

    Google Scholar 

  53. Han, Y., Weinman, S., Boldogh, I., Walker, R. K., and Braiser, A. R. 1999. Tumor Necrosis Factor-α-inducible IkBα proteolysis mediated by cytosolic m-calpain. J. Biol. Chem. 274:787–794.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Medical University of South Carolina, Charleston, SC, 29425

    K. E. Schaecher, D. C. Shields & N. L. Banik

Authors
  1. K. E. Schaecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. C. Shields
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. L. Banik
    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

Schaecher, K.E., Shields, D.C. & Banik, N.L. Mechanism of Myelin Breakdown in Experimental Demyelination: A Putative Role for Calpain. Neurochem Res 26, 731–737 (2001). https://doi.org/10.1023/A:1010903823668

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1010903823668

Search

Navigation