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Prion protein and its role in signal transduction

Abstract

Prion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their etiologic agent: prions (PrPSc). A prion is an infectious protein with the ability to convert the host-encoded cellular prion protein (PrPC) into new prion molecules by acting as a template. Since Stanley B. Prusiner proposed the “protein-only” hypothesis for the first time, considerable effort has been put into defining the role played by PrPC in neurons. However, its physiological function remains unclear. This review summarizes the major findings that support the involvement of PrPC in signal transduction.

Abbreviations

Ab:

antibody

AD:

Alzheimer’s disease

BSE:

bovine spongiform encephalopathy

cAMP:

cyclic adenosine mono-phosphate

CJD:

Creutzfeldt-Jakob disease

CNS:

central nervous system

CWD:

chronic wasting disease

ER:

endoplasmic reticulum

ERK:

extracellular signal-related kinase

FFI:

fatal familial insomnia

GPI:

glycophosphatidylinositol

GSS:

Gerstmann-Sträussler-Scheinker syndrome

ICAT:

isotope-coded affinity tagging

LR:

laminin receptor

LRP:

laminin receptor precursor

MAP:

mitogen-activated protein

MEK:

MAP/ERK kinase

MHC:

major histocompatibility complex

NADPH:

nicotinamide adenine dinucleotide phosphate

NCAM:

neural cell adhesion molecule

NMDA:

N-methyl-D-aspartate

PI3K:

phosphatidylinositol 3-kinase

PKA:

protein kinase A

PKC:

protein kinase C

PMCA:

plasma membrane calcium ATPase

PrP:

prion protein

PrPC :

cellular prion protein

PrPSc :

prion

ROS:

reactive oxygen species

RPTPα:

receptor protein tyrosine phosphatase α

SERCA:

sarco/endoplasmic reticulum calcium ATPase

STI1:

stressinducible protein 1

TSE:

transmissible spongiform encephalopathy

VGCC:

voltagegated calcium channel

References

  1. Gajdusek, D.C. Unconventional viruses and the origin and disappearance of kuru. Science 197 (1977) 943–960.

    PubMed  CAS  Article  Google Scholar 

  2. Prusiner, S.B. Molecular structure, biology, and genetics of prions. Adv. Virus. Res. 35 (1988) 83–136.

    PubMed  CAS  Article  Google Scholar 

  3. Pan, K.M., Baldwin, M., Nguyen, J., Gasset, M., Serban, A., Groth, D., Mehlhorn, I., Huang, Z., Fletterick, R.J. and Cohen, F.E. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc. Natl. Acad. Sci. USA 90 (1993) 10962–10966.

    PubMed  CAS  Article  Google Scholar 

  4. Benetti, F. and Legname, G. De novo mammalian prion synthesis. Prion 3 (2009) 213–219.

    PubMed  CAS  Article  Google Scholar 

  5. Cohen, F.E., Pan, K.M., Huang, Z., Baldwin, M., Fletterick, R.J. and Prusiner, S.B. Structural clues to prion replication. Science 264 (1994) 530–531.

    PubMed  CAS  Article  Google Scholar 

  6. Prusiner, S.B., Groth, D.F., Bolton, D.C., Kent, S.B. and Hood, L.E. Purification and structural studies of a major scrapie prion protein. Cell 38 (1984) 127–134.

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  8. Gabriel, J.M., Oesch, B., Kretzschmar, H., Scott, M. and Prusiner, S.B. Molecular cloning of a candidate chicken prion protein. Proc. Natl. Acad. Sci. USA 89 (1992) 9097–9101.

    PubMed  CAS  Article  Google Scholar 

  9. Schatzl, H.M., Da Costa, M., Taylor, L., Cohen, F.E. and Prusiner, S.B. Prion protein gene variation among primates. J. Mol. Biol. 245 (1995) 362–374.

    PubMed  CAS  Article  Google Scholar 

  10. Basler, K., Oesch, B., Scott, M., Westaway, D., Wälchli, M., Groth, D.F., McKinley, M.P., Prusiner, S.B. and Weissmann, C. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell 46 (1986) 417–428.

    PubMed  CAS  Article  Google Scholar 

  11. Kretzschmar, H.A., Prusiner, S.B., Stowring, L.E. and DeArmond, S.J. Scrapie prion proteins are synthesized in neurons. Am. J. Pathol. 122 (1986) 1–5.

    PubMed  CAS  Google Scholar 

  12. Viles, J.H., Cohen, F.E., Prusiner, S.B., Goodin, D.B., Wright, P.E. and Dyson, H.J. Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc. Natl. Acad. Sci. USA 96 (1999) 2042–2047.

    PubMed  CAS  Article  Google Scholar 

  13. Zahn, R., Liu, A., Luhrs, T., Riek, R., von Schroetter, C., Garcia, F.L., Billeter, M., Calzolai, L., Wider, G. and Wüthrich, K. NMR solution structure of the human prion protein. Proc. Natl. Acad. Sci. USA 97 (2000) 145–150.

    PubMed  CAS  Article  Google Scholar 

  14. Stahl, N., Baldwin, M.A., Burlingame, A.L. and Prusiner, S.B. Identification of glycoinositol phospholipid linked and truncated forms of the scrapie prion protein. Biochemistry 29 (1990) 8879–8884.

    PubMed  CAS  Article  Google Scholar 

  15. Vey, M., Pilkuhn, S., Wille, H., Nixon, R., DeArmond, S.J., Smart, E.J., Anderson, R.G.W., Taraboulos, A. and Prusiner, S.B. Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains. Proc. Natl. Acad. Sci. USA 93 (1996) 14945–14949.

    PubMed  CAS  Article  Google Scholar 

  16. Naslavsky, N., Stein, R., Yanai, A., Friedlander, G. and Taraboulos, A. Characterization of detergent-insoluble complexes containing the cellular prion protein and its scrapie isoform. J. Biol. Chem. 272 (1997) 6324–6331.

    PubMed  CAS  Article  Google Scholar 

  17. Shyng, S.L., Huber, M.T. and Harris, D.A. A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells. J. Biol. Chem. 268 (1993) 15922–15928.

    PubMed  CAS  Google Scholar 

  18. Anderson, R.G. The caveolae membrane system. Annu. Rev. Biochem. 67 (1998) 199–225.

    PubMed  CAS  Article  Google Scholar 

  19. Taylor, D.R. and Hooper, N.M. The prion protein and lipid rafts. Mol. Membr. Biol. 23 (2006) 89–99.

    PubMed  CAS  Article  Google Scholar 

  20. Borchelt, D.R., Taraboulos, A. and Prusiner, S.B. Evidence for synthesis of scrapie prion proteins in the endocytic pathway. J. Biol. Chem. 267 (1992) 16188–16199.

    PubMed  CAS  Google Scholar 

  21. Didonna, A., Vaccari, L., Bek, A. and Legname, G. Infrared microspectroscopy: a multiple-screening platform for investigating singlecell biochemical perturbations upon prion infection. ACS Chem. Neurosci. 2 (2011) 160–174.

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  23. Manson, J.C., Clarke, A.R., Hooper, M.L., Aitchison, L., McConnell, I. and Hope, J. 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol. Neurobiol. 8 (1994) 121–127.

    PubMed  CAS  Article  Google Scholar 

  24. Tobler, I., Gaus, S.E., Deboer, T., Achermann, P., Fischer, M., Rülicke, T., Moser, M., Oesch, B., McBride, P.A. and Manson, J.C. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380 (1996) 639–642.

    PubMed  CAS  Article  Google Scholar 

  25. Coitinho, A.S., Roesler, R., Martins, V.R., Brentani, R.R. and Izquierdo, I. Cellular prion protein ablation impairs behavior as a function of age. Neuroreport 14 (2003) 1375–1379.

    PubMed  Google Scholar 

  26. Criado, J.R., Sánchez-Alavez, M., Conti, B., Giacchino, J.L., Wills, D.N., Henriksen, S.J., Race, R., Manson, J.C., Chesebro, B. and Oldstone, M.B. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol. Dis. 19 (2005) 255–265.

    PubMed  CAS  Article  Google Scholar 

  27. Sakaguchi, S., Katamine, S., Nishida, N., Moriuchi, R., Shigematsu, K., Sugimoto, T., Nakatani, A., Kataoka, Y., Houtani, T., Shirabe, S., Okada, H., Hasegawa, S., Miyamoto, T. and Noda, T. Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 380 (1996) 528–531.

    PubMed  CAS  Article  Google Scholar 

  28. 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. Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J. Mol. Biol. 292 (1999) 797–817.

    PubMed  CAS  Article  Google Scholar 

  29. Didonna, A., Sussman, J., Benetti, F. and Legname, G. The role of Bax and caspase-3 in doppel-induced apoptosis of cerebellar granule cells. Prion 6 (2012) 309–316.

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  31. Richt, J.A., Kasinathan, P., Hamir, A.N., Castilla, J., Sathiyaseelan, T., Vargas, F., Sathiyaseelan, J., Wu, H., Matsushita, H., Koster, J., Kato, S., Ishida, I., Soto, C., Robl, J.M. and Kuroiwa, Y. Production of cattle lacking prion protein. Nat. Biotechnol. 25 (2007) 132–138.

    PubMed  CAS  Article  Google Scholar 

  32. Yu, G., Chen, J., Xu, Y., Zhu, C., Yu, H., Liu, S., Sha, H., Chen, J., Xu, X., Wu, Y., Zhang, A., Ma, J. and Cheng, G. Generation of goats lacking prion protein. Mol. Reprod. Dev. 76 (2009) 3.

    PubMed  CAS  Article  Google Scholar 

  33. Bueler, H., Aguzzi, A., Sailer, A., Greiner, R.A., Autenried, P., Aguet, M. and Weissmann, C. Mice devoid of PrP are resistant to scrapie. Cell 73 (1993) 1339–1347.

    PubMed  CAS  Article  Google Scholar 

  34. Malaga-Trillo, E., Solis, G.P., Schrock, Y., Geiss, C., Luncz, L., Thomanetz, V. and Stuermer, C.A. Regulation of embryonic cell adhesion by the prion protein. PLOS Biol. 7 (2009) e55.

    PubMed  Article  CAS  Google Scholar 

  35. 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. The cellular prion protein binds copper in vivo. Nature 390 (1997) 684–687.

    PubMed  CAS  Article  Google Scholar 

  36. Brown, D.R., Clive, C. and Haswell, S.J. Antioxidant activity related to copper binding of native prion protein. J. Neurochem. 76 (2001) 69–76.

    PubMed  CAS  Article  Google Scholar 

  37. Tobler, I., Deboer, T. and Fischer, M. Sleep and sleep regulation in normal and prion protein-deficient mice. J. Neurosci. 17 (1997) 1869–1879.

    PubMed  CAS  Google Scholar 

  38. Le Pichon, C.E., Valley, M.T., Polymenidou, M., Chesler, A.T., Sagdullaev, B.T., Aguzzi, A. and Firestein, S. Olfactory behavior and physiology are disrupted in prion protein knockout mice. Nat. Neurosci. 12 (2009) 60–69.

    PubMed  Article  CAS  Google Scholar 

  39. Bremer, J., Baumann, F., Tiberi, C., Wessig, C., Fischer, H., Schwarz, P., Steele, A.D., Toyka, K.V., Nave, K.A., Weis, J. and Aguzzi, A. Axonal prion protein is required for peripheral myelin maintenance. Nat. Neurosci. 13 (2010) 310–318.

    PubMed  CAS  Article  Google Scholar 

  40. Zhang, C.C., Steele, A.D., Lindquist, S. and Lodish, H.F. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc. Natl. Acad. Sci. USA 103 (2006) 2184–2189.

    PubMed  CAS  Article  Google Scholar 

  41. Isaacs, J.D., Jackson, G.S. and Altmann, D.M. The role of the cellular prion protein in the immune system. Clin. Exp. Immunol. 146 (2006) 1–8.

    PubMed  CAS  Article  Google Scholar 

  42. Shmerling, D., Hegyi, I., Fischer, M., Blättler, T., Brandner, S., Götz, J., Rülicke, T., Flechsig, E., Cozzio, A., von Mering, C., Hangartner, C., Aguzzi, A. and Weissmann, C. Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93 (1998) 203–214.

    PubMed  CAS  Article  Google Scholar 

  43. Simons, K. and Toomre, D. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1 (2000) 31–39.

    PubMed  CAS  Article  Google Scholar 

  44. Pawson, T. Protein modules and signalling networks. Nature 373 (1995) 573–580.

    PubMed  CAS  Article  Google Scholar 

  45. Aguzzi, A., Baumann, F. and Bremer, J. The prion’s elusive reason for being. Annu. Rev. Neurosci. 31 (2008) 439–477.

    PubMed  CAS  Article  Google Scholar 

  46. Schmitt-Ulms, G., Legname, G., Baldwin, M.A., Ball, H.L., Bradon, N., Bosque, P.J., Crossin, K.L., Edelman, G.M., DeArmond, S.J., Cohen, F.E. and Prusiner, S.B. Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J. Mol. Biol. 314 (2001) 1209–1225.

    PubMed  CAS  Article  Google Scholar 

  47. Gauczynski, S., Peyrin, J.M., Haïk, S., Leucht, C., Hundt, C., Rieger, R., Krasemann, S., Deslys, J.P., Dormont, D., Lasmézas, C.I. and Weiss, S. The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J. 20 (2001) 5863–5875.

    PubMed  CAS  Article  Google Scholar 

  48. 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. Cellular prion protein binds laminin and mediates neuritogenesis. Brain Res. Mol. Brain Res. 76 (2000) 85–92.

    PubMed  CAS  Article  Google Scholar 

  49. Martins, V.R., Graner, E., Garcia-Abreu, J., de Souza, S.J., Mercadante, A.F., Veiga, S.S., Zanata, S.M., Neto, V.M. and Brentani, R.R. Complementary hydropathy identifies a cellular prion protein receptor. Nat. Med. 3 (1997) 1376–1382.

    PubMed  CAS  Article  Google Scholar 

  50. 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., de Oliveira, E., Jachieri, S.G., Burlingame, A., Huang, L., Linden, R., Brentani, R.R. and Martins, V.R. Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J. 21 (2002) 3307–3316.

    PubMed  CAS  Article  Google Scholar 

  51. Rutishauser, D., Mertz, K.D., Moos, R., Brunner, E., Rulicke, T., Calella, A.M. and Aguzzi, A. The comprehensive native interactome of a fully functional tagged prion protein. PLOS One 4 (2009) e4446.

    PubMed  Article  CAS  Google Scholar 

  52. Lauren, J., Gimbel, D.A., Nygaard, H.B., Gilbert, J.W. and Strittmatter, S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457 (2009) 1128–1132.

    PubMed  CAS  Article  Google Scholar 

  53. Kessels, H.W., Nguyen, L.N., Nabavi, S. and Malinow, R. The prion protein as a receptor for amyloid-beta. Nature 466 (2010) E3–4; discussion E4–5.

    PubMed  CAS  Article  Google Scholar 

  54. Balducci, C., Beeg, M., Stravalaci, M., Bastone, A., Sclip, A., Biasini, E., Tapella, L., Colombo, L., Manzoni, C., Borsello, T., Chiesa, R., Gobbi, M., Salmona, M. and Forloni, G. Synthetic amyloid-beta oligomers impair longterm memory independently of cellular prion protein. Proc. Natl. Acad. Sci. USA 107 (2010) 2295–2300.

    PubMed  CAS  Article  Google Scholar 

  55. Calella, A.M., Farinelli, M., Nuvolone, M., Mirante, O., Moos, R., Falsig, J., Mansuy, I.M. and Aguzzi, A. Prion protein and Abeta-related synaptic toxicity impairment. EMBO Mol. Med. 2 (2010) 306–314.

    PubMed  CAS  Article  Google Scholar 

  56. Mouillet-Richard, S., Ermonval, M., Chebassier, C., Laplanche, J.L., Lehmann, S., Launay, J.M. and Kellermann, O. Signal transduction through prion protein. Science 289 (2000) 1925–1928.

    PubMed  CAS  Article  Google Scholar 

  57. Yeatman, T.J. A renaissance for SRC. Nat. Rev. Cancer 4 (2004) 470–480.

    PubMed  CAS  Article  Google Scholar 

  58. Beggs, H.E., Soriano, P. and Maness, P.F. NCAM-dependent neurite outgrowth is inhibited in neurons from Fyn-minus mice. J. Cell Biol. 127 (1994) 825–833.

    PubMed  CAS  Article  Google Scholar 

  59. Santuccione, A., Sytnyk, V., Leshchyns’ka, I. and Schachner, M. Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J. Cell Biol. 169 (2005) 341–354.

    PubMed  CAS  Article  Google Scholar 

  60. Kanaani, J., Prusiner, S.B., Diacovo, J., Baekkeskov, S. and Legname, G. Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro. J. Neurochem. 95 (2005) 1373–1386.

    PubMed  CAS  Article  Google Scholar 

  61. Schwarz, A., Burwinkel, M., Riemer, C., Schultz, J. and Baier, M. Unchanged scrapie pathology in brain tissue of tyrosine kinase Fyn-deficient mice. Neurodegener. Dis. 1 (2004) 266–268.

    PubMed  CAS  Article  Google Scholar 

  62. Nixon, R.R. Prion-associated increases in Src-family kinases. J. Biol. Chem. 280 (2005) 2455–2462.

    PubMed  CAS  Article  Google Scholar 

  63. Gyllberg, H., Lofgren, K., Lindegren, H. and Bedecs, K. Increased Src kinase level results in increased protein tyrosine phosphorylation in scrapieinfected neuronal cell lines. FEBS Lett. 580 (2006) 2603–2608.

    PubMed  CAS  Article  Google Scholar 

  64. Didonna, A. and Legname, G. Aberrant ERK 1/2 complex activation and localization in scrapie-infected GT1-1 cells. Mol. Neurodegener. 5 (2010) 29.

    PubMed  Article  CAS  Google Scholar 

  65. Um, J.W., Nygaard, H.B., Heiss, J.K., Kostylev, M.A., Stagi, M., Vortmeyer, A., Wisniewski, T., Gunther, E.C. and Strittmatter, S.M. Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15 (2012) 1227–1235.

    PubMed  CAS  Article  Google Scholar 

  66. Schneider, B., Mutel, V., Pietri, M., Ermonval, M., Mouillet-Richard, S. and Kellermann, O. NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells. Proc. Natl. Acad. Sci. USA 100 (2003) 13326–13331.

    PubMed  CAS  Article  Google Scholar 

  67. Suganuma, T. and Workman, J.L. MAP kinases and histone modification. J. Mol. Cell. Biol. 34 (2010) 1543–1551.

    Google Scholar 

  68. Lopes, M.H., Hajj, G.N., Muras, A.G., Mancini, G.L., Castro, R.M., Ribeiro, K.C., Brentani, R.R., Linden, R. and Martins, V.R. Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J. Neurosci. 25 (2005) 11330–11339.

    PubMed  CAS  Article  Google Scholar 

  69. Pietri, M., Caprini, A., Mouillet-Richard, S., Pradines, E., Ermonval, M., Grassi, J., Kellermann, O. and Schneider, B. Overstimulation of PrPC signaling pathways by prion peptide 106–126 causes oxidative injury of bioaminergic neuronal cells. J. Biol. Chem. 281 (2006) 28470–28479.

    PubMed  CAS  Article  Google Scholar 

  70. Marella, M., Gaggioli, C., Batoz, M., Deckert, M., Tartare-Deckert, S. and Chabry, J. Pathological prion protein exposure switches on neuronal mitogen-activated protein kinase pathway resulting in microglia recruitment. J. Biol. Chem. 280 (2005) 1529–1534.

    PubMed  CAS  Article  Google Scholar 

  71. Lee, H.P., Jun, Y.C., Choi, J.K., Kim, J.I., Carp, R.I. and Kim, Y.S. Activation of mitogen-activated protein kinases in hamster brains infected with 263K scrapie agent. J. Neurochem. 95 (2005) 584–593.

    PubMed  CAS  Article  Google Scholar 

  72. Carimalo, J., Cronier, S., Petit, G., Peyrin, J.M., Boukhtouche, F., Arbez, N., Lemaigre-Dubreuil, Y., Brugg, B. and Miquel, M.C. Activation of the JNKc-Jun pathway during the early phase of neuronal apoptosis induced by PrP106–126 and prion infection. Eur. J. Neurosci. 21 (2005) 2311–2319.

    PubMed  CAS  Article  Google Scholar 

  73. Thellung, S., Villa, V., Corsaro, A., Pellistri, F., Venezia, V., Russo, C., Aceto, A., Robello, M. and Florio, T. ERK1/2 and p38 MAP kinases control prion protein fragment 90–231-induced astrocyte proliferation and microglia activation. Glia 55 (2007) 1469–1485.

    PubMed  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  75. Nordstrom, E.K., Luhr, K.M., Ibanez, C. and Kristensson, K. Inhibitors of the mitogen-activated protein kinase kinase 1/2 signaling pathway clear prion-infected cells from PrPSc. J. Neurosci. 25 (2005) 8451–8456.

    PubMed  Article  CAS  Google Scholar 

  76. Uppington, K.M. and Brown, D.R. Resistance of cell lines to prion toxicity aided by phospho-ERK expression. J. Neurochem. 105 (2008) 842–852.

    PubMed  CAS  Article  Google Scholar 

  77. Pidoux, G. and Tasken, K. Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. J. Mol. Endocrinol. 44 (2010) 271–284.

    PubMed  CAS  Article  Google Scholar 

  78. Howe, A.K. Cross-talk between calcium and protein kinase A in the regulation of cell migration. Curr. Opin. Cell Biol. 23 (2011) 554–561.

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  80. Coitinho, A.S., Freitas, A.R., Lopes, M.H., Hajj, G.N., Roesler, R., Walz, R., Rossato, J.I., Cammarota, M., Izquierdo, I., Martins, V.R. and Brentani, R.R. The interaction between prion protein and laminin modulates memory consolidation. Eur. J. Neurosci. 24 (2006) 3255–3264.

    PubMed  Article  Google Scholar 

  81. Kang, J.H., Toita, R., Kim, C.W. and Katayama, Y. Protein kinase C (PKC) isozyme-specific substrates and their design. Biotechnol. Adv. 30 (2012) 1662–1672.

    PubMed  CAS  Article  Google Scholar 

  82. Zhang, B. and Xia, C. 12-O-tetradecanoylphorbol-1, 3-acetate induces the negative regulation of protein kinase B by protein kinase Calpha during gastric cancer cell apoptosis. Cell. Mol. Biol. Lett. 15 (2010) 377–394.

    PubMed  CAS  Article  Google Scholar 

  83. Mazzoni, I.E., Ledebur, H.C., Jr., Paramithiotis, E. and Cashman, N. Lymphoid signal transduction mechanisms linked to cellular prion protein. Biochem. Cell. Biol. 83 (2005) 644–653.

    PubMed  CAS  Article  Google Scholar 

  84. Botto, L., Masserini, M., Cassetti, A. and Palestini, P. Immunoseparation of prion protein-enriched domains from other detergent-resistant membrane fractions, isolated from neuronal cells. FEBS Lett. 557 (2004) 143–147.

    PubMed  CAS  Article  Google Scholar 

  85. Rodriguez, A., Martin, M., Albasanz, J.L., Barrachina, M., Espinosa, J.C., Torres, J.M. and Ferrer, I. Group I mGluR signaling in BSE-infected bovine-PrP transgenic mice. Neurosci. Lett. 410 (2006) 115–120.

    PubMed  CAS  Article  Google Scholar 

  86. Bartholomeusz, C. and Gonzalez-Angulo, A.M. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16 (2012) 121–130.

    PubMed  CAS  Article  Google Scholar 

  87. Huang, J.G., Xia, C., Zheng, X.P., Yi, T.T., Wang, X.Y., Song, G. and Zhang, B. 17beta-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway. Cell. Mol. Biol. Lett. 16 (2011) 564–575.

    PubMed  CAS  Article  Google Scholar 

  88. Chen, S., Mange, A., Dong, L., Lehmann, S. and Schachner, M. Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. Mol. Cell. Neurosci. 22 (2003) 227–233.

    PubMed  CAS  Article  Google Scholar 

  89. Weise, J., Sandau, R., Schwarting, S., Crome, O., Wrede, A., Schulz-Schaeffer, W., Zerr, I. and Bahr, M. Deletion of cellular prion protein results in reduced Akt activation, enhanced postischemic caspase-3 activation, and exacerbation of ischemic brain injury. Stroke 37 (2006) 1296–1300.

    PubMed  CAS  Article  Google Scholar 

  90. Weise, J., Doeppner, T.R., Muller, T., Wrede, A., Schulz-Schaeffer, W., Zerr, I., Witte, O.W. and Bahr, M. Overexpression of cellular prion protein alters postischemic Erk1/2 phosphorylation but not Akt phosphorylation and protects against focal cerebral ischemia. Restor. Neurol. Neurosci. 26 (2008) 57–64.

    PubMed  CAS  Google Scholar 

  91. Vassallo, N., Herms, J., Behrens, C., Krebs, B., Saeki, K., Onodera, T., Windl, O. and Kretzschmar, H.A. Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival. Biochem. Biophys. Res. Commun. 332 (2005) 75–82.

    PubMed  CAS  Article  Google Scholar 

  92. Schmalzbauer, R., Eigenbrod, S., Winoto-Morbach, S., Xiang, W., Schutze, S., Bertsch, U. and Kretzschmar, H.A. Evidence for an association of prion protein and sphingolipid-mediated signaling. J. Neurochem. 106 (2008) 1459–1470.

    PubMed  CAS  Article  Google Scholar 

  93. Seo, J.S., Seol, J.W., Moon, M.H., Jeong, J.K., Lee, Y.J. and Park, S.Y. Hypoxia protects neuronal cells from human prion protein fragment-induced apoptosis. J. Neurochem. 112 (2010) 715–722.

    PubMed  CAS  Article  Google Scholar 

  94. Roffe, M., Beraldo, F.H., Bester, R., Nunziante, M., Bach, C., Mancini, G., Gilch, S., Vorberg, I., Castilho, B.A., Martins, V.R. and Hajj, G.N. Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR. Proc. Natl. Acad. Sci. USA 107 (2010) 13147–13152.

    PubMed  CAS  Article  Google Scholar 

  95. Munaron, L. and Scianna, M. Multilevel complexity of calcium signaling: Modeling angiogenesis. World J. Biol. Chem. 3 (2012) 121–126.

    PubMed  Article  Google Scholar 

  96. Peggion, C., Bertoli, A. and Sorgato, M.C. Possible role for Ca2+ in the pathophysiology of the prion protein? Biofactors 37 (2011) 241–249.

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  98. Herms, J.W., Korte, S., Gall, S., Schneider, I., Dunker, S. and Kretzschmar, H.A. Altered intracellular calcium homeostasis in cerebellar granule cells of prion protein-deficient mice. J. Neurochem. 75 (2000) 1487–1492.

    PubMed  CAS  Article  Google Scholar 

  99. Herms, J.W., Tings, T., Dunker, S. and Kretzschmar, H.A. Prion protein affects Ca2+-activated K+ currents in cerebellar purkinje cells. Neurobiol. Dis. 8 (2001) 324–330.

    PubMed  CAS  Article  Google Scholar 

  100. Fuhrmann, M., Bittner, T., Mitteregger, G., Haider, N., Moosmang, S., Kretzschmar, H. and Herms, J. Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons. J. Neurochem. 98 (2006) 1876–1885.

    PubMed  CAS  Article  Google Scholar 

  101. Whatley, S.A., Powell, J.F., Politopoulou, G., Campbell, I.C., Brammer, M.J. and Percy, N.S. Regulation of intracellular free calcium levels by the cellular prion protein. Neuroreport 6 (1995) 2333–2337.

    PubMed  CAS  Article  Google Scholar 

  102. Korte, S., Vassallo, N., Kramer, M.L., Kretzschmar, H.A. and Herms, J. Modulation of L-type voltage-gated calcium channels by recombinant prion protein. J. Neurochem. 87 (2003) 1037–1042.

    PubMed  CAS  Article  Google Scholar 

  103. Powell, A.D., Toescu, E.C., Collinge, J. and Jefferys, J.G. Alterations in Ca2+-buffering in prion-null mice: association with reduced afterhyperpolarizations in CA1 hippocampal neurons. J. Neurosci. 28 (2008) 3877–3886.

    PubMed  CAS  Article  Google Scholar 

  104. Lazzari, C., Peggion, C., Stella, R., Massimino, M.L., Lim, D., Bertoli, A. and Sorgato, M.C. Cellular prion protein is implicated in the regulation of local Ca2+ movements in cerebellar granule neurons. J. Neurochem. 116 (2011) 881–890.

    PubMed  CAS  Article  Google Scholar 

  105. Mattson, M.P. Calcium and neurodegeneration. Aging Cell 6 (2007) 337–350.

    PubMed  CAS  Article  Google Scholar 

  106. Kristensson, K., Feuerstein, B., Taraboulos, A., Hyun, W.C., Prusiner, S.B. and DeArmond, S.J. Scrapie prions alter receptor-mediated calcium responses in cultured cells. Neurology 43 (1993) 2335–2341.

    PubMed  CAS  Article  Google Scholar 

  107. Barrow, P.A., Holmgren, C.D., Tapper, A.J. and Jefferys, J.G. Intrinsic physiological and morphological properties of principal cells of the hippocampus and neocortex in hamsters infected with scrapie. Neurobiol. Dis. 6 (1999) 406–423.

    PubMed  CAS  Article  Google Scholar 

  108. Johnston, A.R., Fraser, J.R., Jeffrey, M. and MacLeod, N. Alterations in potassium currents may trigger neurodegeneration in murine scrapie. Exp. Neurol. 151 (1998) 326–333.

    PubMed  CAS  Article  Google Scholar 

  109. Florio, T., Thellung, S., Amico, C., Robello, M., Salmona, M., Bugiani, O., Tagliavini, F., Forloni, G. and Schettini, G. Prion protein fragment 106–126 induces apoptotic cell death and impairment of L-type voltage-sensitive calcium channel activity in the GH3 cell line. J. Neurosci. Res. 54 (1998) 341–352.

    PubMed  CAS  Article  Google Scholar 

  110. Thellung, S., Florio, T., Villa, V., Corsaro, A., Arena, S., Amico, C., Robello, M., Salmona, M., Forloni, G., Bugiani, O., Tagliavini, F. and Schettini, G. Apoptotic cell death and impairment of L-type voltagesensitive calcium channel activity in rat cerebellar granule cells treated with the prion protein fragment 106–126. Neurobiol. Dis. 7 (2000) 299–309.

    PubMed  CAS  Article  Google Scholar 

  111. Sandberg, M.K., Wallen, P., Wikstrom, M.A. and Kristensson, K. Scrapieinfected GT1-1 cells show impaired function of voltage-gated N-type calcium channels (Ca(v) 2.2) which is ameliorated by quinacrine treatment. Neurobiol. Dis. 15 (2004) 143–151.

    PubMed  CAS  Article  Google Scholar 

  112. Torres, M., Castillo, K., Armisen, R., Stutzin, A., Soto, C. and Hetz, C. Prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress. PLOS One 5 (2010) e15658.

    PubMed  CAS  Article  Google Scholar 

  113. Gray, F., Adle-Biassette, H., Chretien, F., Ereau, T., Delisle, M.B. and Vital, C. Neuronal apoptosis in human prion diseases. Bull. Acad. Natl. Med. 183 (1999) 305–320; discussion 320–301.

    PubMed  CAS  Google Scholar 

  114. Ojcius, D.M., Delarbre, C., Kourilsky, P. and Gachelin, G. MHC and MHCrelated proteins as pleiotropic signal molecules. FASEB J. 16 (2002) 202–206.

    PubMed  CAS  Article  Google Scholar 

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Didonna, A. Prion protein and its role in signal transduction. Cell Mol Biol Lett 18, 209–230 (2013). https://doi.org/10.2478/s11658-013-0085-0

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Key words

  • Prion
  • PrPC
  • PrPSc
  • Src
  • MAP kinases
  • PKA
  • PKC
  • AKT
  • Calcium
  • Signaling