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Cellular Prion Protein: Implications in Seizures and Epilepsy

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Abstract

1. Cellular prion (PrPc) is a plasma membrane protein involved with copper uptake, protection against oxidative stress, cell adhesion, differentiation, signaling, and survival in the central nervous system

2. Deletion of PrPc gene (Prnp) in mice enhances sensitivity to seizures in vivo and neuronal excitability in vitro which can be related to: (i) disrupted Ca+2-activated K+ currents, with loss of I HAP conductance in hippocampus; (ii) abnormal GABA-A inhibition in the hippocampus; (iii) mossy fiber reorganization in the hippocampus; (iv) changes in ectonucleotidases in both hippocampus and neocortex; and (v) higher levels of neocortical and subcortical oxidative stress. Moreover, postnatal Prnp knockout mice showed a significant reduction of after hyperpolarization potentials in hippocampal CA1 cells.

3. Taken together, these findings suggest that loss of PrPc function contributes to the hyperexcitable and synchronized activities underlying epileptic seizures generated in neocortex and hippocampus. Hence, the role of PrPc on human symptomatic, cryptogenic or idiopathic epileptic syndromes deserves further investigation.

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REFERENCES

  • Baranes, D., Lederfein, D., Huang, Y. Y., Chen, M., Bailey, C. H., and Kandel, E. R. (1998). Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21:813–825.

    Google Scholar 

  • Ben-Ari, Y. (1985). Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403.

    Google Scholar 

  • Bonan, C. D., Amaral, O. B., Rockenbach, I. C.,Walz, R., Battastini, A. M., Izquierdo, I., and Sarkis, J. J. (2000a). Altered ATP hydrolysis induced by pentylenetetrazol kindling in rat brain synaptosomes. Neurochem. Res. 25:775–779.

    Google Scholar 

  • Bonan, C. D., Walz, R., Pereira, G. S., Worm, P. V., Battastini, A. M., Cavalheiro, E. A., Izquierdo, I., and Sarkis, J. J. (2000b). Changes in synaptosomal ectonucleotidase activities in two rat models of temporal lobe epilepsy. Epilepsy Res. 39:229–238.

    Google Scholar 

  • Bounhar, Y., Zhang, Y., Goodyer, C. G., and LeBlanc, A. (2001). Prion protein protects human neurons against Bax-mediated apoptosis. J. Biol. Chem. 276:39145–39149.

    Google Scholar 

  • Brown, D. R., Qin, K., Herms, J. W., Madlung, A., Manson, J., Strome, R., Fraser, P. E., Kruck, T., von Bohlen, A., Schulz-Schaeffer,W., Giese, A., Westaway, D., and Kretzschmar,H. (1997a). The cellular prion protein binds copper in vivo. Nature 390:684–687.

    Google Scholar 

  • Brown, D. R., Schulz-Schaeffer, W. J., Schmidt, B., and Kretzschmar, H.A. (1997b). Prion protein-deficient cells show altered response to oxidative stress due to decreased SOD-1 activity. Exp. Neurol. 146:104–112.

    Google Scholar 

  • Brown, D. R.,Wong, B. S., Hafiz, F., Clive, C., Haswell, S. J., and Jones, I.M. (1999). Normal prion protein has an activity like that of superoxide dismutase. Biochem. J. 344(Pt 1):1–5.

    Google Scholar 

  • Bueler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H. P., DeArmond, S. J., Prusiner, S. B., Aguet, M., and Weissmann, C. (1992). Normal development and behaviour of mice lacking the neuronal cellsurface PrP protein. Nature 356:577–582.

    Google Scholar 

  • Cavalheiro, E. A., Leite, J. P., Bortolotto, Z. A., Turski, W. A., Ikonomidou, C., and Turski, L. (1991). Longterm effects of pilocarpine in rats: Structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 32:778–782.

    Google Scholar 

  • Chen, Z. L., and Strickland, S. (1997). Neuronal death in the hippocampus is promoted by plasmincatalyzed degradation of laminin. Cell 91:917–925.

    Google Scholar 

  • Chiarini, L. B., Freitas, A. R. O., Zanata, S. M., Brentani R. R., Martins, V. R., and Linden, R. (2002). Cellular prion protein transduces neuroprotective signals. EMBO J. 21:3317–3326.

    Google Scholar 

  • Clarke, G., Collins, R. A., Leavitt, B. R., Andrews, D. F., Hayden, M. R., Lumsden, C. J., and McInnes, R. R. (2000). A one-hit model of cell death in inherited neuronal degenerations. Nature 406:195–199.

    Google Scholar 

  • Colling, S. B., Collinge, J., and Jefferys, J. G. (1996). Hippocampal slices from prion protein null mice: Disrupted Ca(2C)-activated KC currents. Neurosci. Lett. 209:49–52.

    Google Scholar 

  • Colling, S. B., Khana, M., Collinge, J., and Jefferys, J. G. (1997). Mossy fibre reorganization in the hippocampus of prion protein null mice. Brain Res. 755:28–35.

    Google Scholar 

  • Collinge, J., Whittington, M. A., Sidle, K. C., Smith, C. J., Palmer, M. S., Clarke, A. R., and Jefferys, J. G. (1994). Prion protein is necessary for normal synaptic function. Nature 370:295–297.

    Google Scholar 

  • Connors, B.W. (1997). Neocortical anatomy and physiology. In Engel, J., and Pedley, T.A. (eds.), Epilepsy: A Comprehensive Textbook, Lippincott-Raven, Philadelphia, pp. 303–321.

    Google Scholar 

  • Connors, B.W., and Gutnick, M. J. (1990). Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci. 13:99–104.

    Google Scholar 

  • Cronin, J., Obenaus, A., Houser, C. R., and Dudek, F. E. (1992). Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of the mossy fibers. Brain Res. 573:305–310.

    Google Scholar 

  • Dal-Pizzol, F., Klamt, F., Vianna, M. M., Schroder, N., Quevedo, J., Benfato, M. S., Moreira, J. C., and Walz, R. (2000). Lipid peroxidation in hippocampus early and late after status epilepticus induced by pilocarpine or kainic acid in Wistar rats. Neurosci. Lett. 291:179–182.

    Google Scholar 

  • Engel, J., Jr. (1996). Surgery for seizures. N. Engl. J. Med. 334:647–652.

    Google Scholar 

  • Engel, J. J. (1989). Mechanisms of neuronal excitation and synchronization. In Engel, J. J. (ed.), Seizures and Epilepsy, Davis, FA, Philadelphia, pp. 41–70.

    Google Scholar 

  • Graner, E., Mercadante, A. F., Zanata, S. M., Forlenza, O. V., Cabral, A. L., Veiga, S. S., Juliano, M. A., Roesler, R., Walz, R., Minetti, A., Izquierdo, I., Martins, V. R., and Brentani, R. R. (2000a). Cellular prion protein binds laminin and mediates neuritogenesis. Brain Res. Mol. Brain. Res. 76:85–92.

    Google Scholar 

  • Graner, E., Mercadante, A. F., Zanata, S. M., Martins, V. R., Jay, D. G., and Brentani, R. R. (2000b). Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett. 482:257–260.

    Google Scholar 

  • Hauser, W. A. (1998). Incidence and Prevalence. In Engel, J., and Pedley, T. A. (eds.), Epilepsy: A Comprehensive Textbook, Lippincott-Raven, Philadelphia, pp. 47–57.

    Google Scholar 

  • ILAE (1989). Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 30:389–399.

    Google Scholar 

  • Jacobs, K. M., Graber, K. D., Kharazia, V. N., Parada, I., and Prince, D. A. (2000). Postlesional epilepsy: The ultimate brain plasticity. Epilepsia 41:S153–161.

    Google Scholar 

  • Klamt, F., Dal-Pizzol, F., Conte da Frota, M. J., Walz, R., Andrades, M. E., da Silva, E. G., Brentani, R. R., Izquierdo, I., and Fonseca Moreira, J. C. (2001). Imbalance of antioxidant defense in mice lacking cellular prion protein. Free Radic. Biol. Med. 30:1137–1144.

    Google Scholar 

  • Kuwahara, C., Takeuchi, A. M., Nishimura, T., Haraguchi, K., Kubosaki, A., Matsumoto, Y., Saeki, K., Yokoyama, T., Itohara, S., and Onodera, T. (1999). Prions prevent neuronal cell-line death. Nature 400:225–226.

    Google Scholar 

  • Lledo, P. M., Tremblay, P., DeArmond, S. J., Prusiner, S. B., and Nicoll, R. A. (1996). Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus. Proc. Natl. Acad. Sci. U.S.A. 93:2403–2407.

    Google Scholar 

  • Llinas, R. R. (1988). The intrinsic electrophysiological properties of mammalian neurons: Insights into central nervous system function. Science 242:1654–1664.

    Google Scholar 

  • Luckenbill-Edds, L. (1997). Laminin and the mechanism of neuronal outgrowth. Brain Res. Brain Res. Rev. 23:1–27.

    Google Scholar 

  • Mallucci, G. R., Ratte, S., Asante, E. A., Linehan, J., Gowland, I., Jefferys, J. G., and Collinge, J. (2002). Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 21:202–210.

    Google Scholar 

  • Martins, V. R., Linden, R., Prado, M. A., Walz, R., Sakamoto, A. C., Izquierdo, I., and Brentani, R. R. (2002). Cellular prion protein: On the road for functions. FEBS Lett. 512:25–28.

    Google Scholar 

  • Martins, V. R., Mercadante, A. F., Cabral, A. L., Freitas, A. R., and Castro, R.M. (2001). Insights into the physiological function of cellular prion protein. Braz. J. Med. Biol. Res. 34:585–595.

    Google Scholar 

  • McCormick, D. A., and Contreras, D. (2001). On the cellular and network bases of epileptic seizures. Annu. Rev. Physiol. 63:815–846.

    Google Scholar 

  • Moore, R. C., Lee, I. Y., Silverman, G. L., Harrison, P. M., Strome, R., Heinrich, C., Karunaratne, A., Pasternak, S. H., Chishti, M. A., Liang, Y., Mastrangelo, P., Wang, K., Smit, A. F., Katamine, S., Carlson, G. A., Cohen, F. E., Prusiner, S. B., Melton, D.W., Tremblay, P., Hood, L. E., and Westaway, D. (1999). Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J. Mol. Biol. 292:797–817.

    Google Scholar 

  • Murray, C. J., Lopez, A. D., and Jamison, D. T. (1994). The global burden of disease in 1990: Summary results, sensitivity analysis and future directions. Bull. World Health Organ. 72:495–509.

    Google Scholar 

  • Oesch, B., Westaway, D., Walchli, M., McKinley, M. P., Kent, S. B., Aebersold, R., Barry, R. A., Tempst, P., Teplow, D. B., and Hood, L. E. (1985). A cellular gene encodes scrapie PrP 27–30 protein. Cell 40:735–746.

    Google Scholar 

  • Pauly, P. C., and Harris, D. A. (1998). Copper stimulates endocytosis of the prion protein. J. Biol. Chem. 273:33107–33110.

    Google Scholar 

  • Pereira, G. S.,Walz, R., Bonan, C. D., Battastini, A. M., Izquierdo, I., Martins, V. R., Brentani, R. R., and Sarkis, J. J. (2001). Changes in cortical and hippocampal ectonucleotidase activities in mice lacking cellular prion protein. Neurosci. Lett. 301:72–74.

    Google Scholar 

  • Prince, D. A., Salin, P., Tseng, G. F., Hoffman, S., and Parada, I. (1997). Axonal sprouting and epileptogenesis. Adv. Neurol. 72:1–8.

    Google Scholar 

  • Prince, D. A., and Tseng, G. F. (1993). Epileptogenesis in chronically injured cortex: In vitro studies. J. Neurophysiol. 69:1276–1291.

    Google Scholar 

  • Prusiner, S. B. (1998). Prions. Proc. Natl. Acad. Sci. U.S.A. 95:13363–13383.

    Google Scholar 

  • Qian, Z., Gilbert, M. E., Colicos, M. A., Kandel, E. R., and Kuhl, D. (1993). Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 361:453–457.

    Google Scholar 

  • Roesler, R., Walz, R., Quevedo, J., de-Paris, F., Zanata, S. M., Graner, E., Izquierdo, I., Martins, V. R., and Brentani, R. R. (1999). Normal inhibitory avoidance learning and anxiety, but increased locomotor activity in mice devoid of PrP(C). Brain Res. Mol. Brain Res. 71:349–353.

    Google Scholar 

  • Rosenow, F., and Luders, H. (2001). Presurgical evaluation of epilepsy. Brain. 124:1683–1700.

    Google Scholar 

  • Sanabria, E. R., Su, H., and Yaari, Y. (2001). Initiation of network bursts by Ca2C-dependent intrinsic bursting in the rat pilocarpine model of temporal lobe epilepsy. J. Physiol. 532:205–216.

    Google Scholar 

  • Schwartkroin, P. A., and McIntyre, D. C. (1997). Limbic Anatomy and Physiology. In Engel, J., and Pedley, T. A. (eds.), Epilepsy: A Comprehensive Textbook, Lippincott-Raven, Philadelphia, pp. 323–340.

  • Walz, R., Amaral, O. B., Rockenbach, I. C., Roesler, R., Izquierdo, I., Cavalheiro, E. A., Martins, V. R., and Brentani, R. R. (1999). Increased sensitivity to seizures in mice lacking cellular prion protein. Epilepsia 40:1679–1682.

    Google Scholar 

  • Wiebe, S., Blume, W. T., Girvin, J. P., and Eliasziw, M. (2001). A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345:311–318.

    Google Scholar 

  • Wong, B. S., Liu, T., Li, R., Pan, T., Petersen, R. B., Smith, M. A., Gambetti, P., Perry, G., Manson, J. C., Brown, D. R., and Sy, M. S. (2001). Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein. J. Neurochem. 76:565–572.

    Google Scholar 

  • Zanata, S. M., Lopes, M. H., Mercadante, A. F., Hajj, G. N. M., Chiarini, L. B., Nomizo, R., Freitas, A. R. O., Cabral, A. L. B., Lee, K. S., Juliano, M. A., Oliveira, E., Jachieri, S. G., Burlingame, A., Huang, L., Linden, R., Brentani, R. R., and Martins, V. R. (2002). Stress Inducible Protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J. 21:3307–3316.

    Google Scholar 

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Authors and Affiliations

  1. CIREP, Center for Epilepsy Surgery, Ribeirão Preto School of Medicine, University Hospital, University of São Paulo, Ribeirão Preto, SP, Brazil

    Roger Walz, Tonicarlo R. Velasco, Carlos G. Carlotti Jr. & Américo C. Sakamoto

  2. Rua Prof. Antônio Prudente 109 4A, Ludwig Institute for Cancer Research, 01509-900, São Paulo, SP, Brazil

    Roger Walz & Ricardo R. Brentani

  3. Centro de Tratamento e Pesquisa Hospital do Câncer, São Paulo, SP, Brazil

    Rosa Maria RPS Castro & Vilma R. Martins

  4. Laboratory of Molecular Biology, Surgery Department, Ribeirão Preto School of Medicine, University Hospital, University of São Paulo, Ribeirão Preto, SP, Brazil

    Carlos G. Carlotti Jr.

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Walz, R., Castro, R.M.R., Velasco, T.R. et al. Cellular Prion Protein: Implications in Seizures and Epilepsy. Cell Mol Neurobiol 22, 249–257 (2002). https://doi.org/10.1023/A:1020711700048

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