Prion Protein, its Role in Cellular Proliferation, Differentiation and Nervous System Development

Czech version

Authors: Z. Hanusová ¹; J. Kučerová ^1,2; M. Filipová ¹; Z. Jindrová ^1,3; K. Holada ¹
Authors‘ workplace: Ústav imunologie a mikrobiologie, 1. LF UK v Praze ¹; Přírodovědecká fakulta, UK v Praze ²; 3. lékařská fakulta UK v Praze ³
Published in: Cesk Slov Neurol N 2015; 78/111(4): 406-412
Category: Review Article

Overview

The cellular prion protein (PrP^C) is well-known for its ability to converse into its pathological isoform, PrP^TSE. Accumulation of PrP^TSE in the brain is associated with pathogenesis of prion diseases. Numerous studies have suggested that PrP^C has a number of physiological functions and participates in many cellular processes. However, convincing evidence is still missing. Possible functions of PrP^C include a role in regulation of apoptosis, protection against oxidative stress, cell adhesion or processes of learning and memory. This protein also seems to influence cell proliferation and differentiation. The level of PrP^C expression during embryonic development affects transcription of genes encoding factors involved in the regulation of stem cells pluripotency at early stages of differentiation. In the nervous system, PrP^C plays an important role in neuronal development, maturation and neural circuit formation. Finally, PrP^C can probably also participate in the differentiation and proliferation of tissue-specific stem cells such as neuronal, hematopoietic or myogenic precursors.

Key words:
prions – prion protein – PrP^C – cell differentiation – cell proliferation – embryonic stem cells – neurons – neurogenesis

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Sources

1. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR. Physiology of the prion protein. Physiol Rev 2008; 88(2): 673– 728. doi: 10.1152/ physrev.00007.2007.

2. Priola SA, Vorberg I. Molecular aspects of disease pathogenesis in the transmissible spongiform encephalopathies. Mol Biotechnol 2006; 33(1): 71– 88.

3. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216(4542): 136– 144.

4. Marandi Y, Farahi N, Sadeghi A, Sadeghi‑ Hashjin G. Prion diseases – current theories and potential therapies: a brief review. Folia Neuropathol 2012; 50(1): 46– 49.

5. Colby DW, Prusiner SB. Prions. Cold Spring Harb Perspect Biol 2011; 3(1): a006833. doi: 10.1101/ cshperspect.a006833.

6. Gdovinová Z. Creutzfeldtova‑ Jakobova choroba. Cesk Slov Neurol N 2013; 76/ 109(2): 138– 153.

7. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A et al. A new variant of Creutzfeldt‑ Jakob disease in the UK. Lancet 1996; 347(9006): 921– 925.

8. Aguzzi A, Calella AM. Prions: Protein aggregation and infectious diseases. Physiol Rev 2009; 89(4): 1105– 1152. doi: 10.1152/ physrev.00006.2009.

9. Rusina R, Fiala J, Holada K, Matejckova M, Novakova J,Ampapa R et al. Gerstmann‑Sträussler‑ Scheinker syndrome with the P102L pathogenic mutation presenting as familial Creutzfeldt‑ Jakob disease: a case report and review of the literature. Neurocase 2013; 19(1): 41– 53. doi: 10.1080/ 13554794.2011.654215.

10. Collins S, McLean CA, Masters CL. Gerstmann‑Sträussler‑ Scheinker syndrome, fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies. J Clin Neurosci 2001; 8(5): 387– 397.

11. Brown P, Brandel JP, Sato T, Nakamura Y, MacKenzie J, Will RG et al. Iatrogenic Creutzfeldt‑ Jakob disease, final assessment. Emerg Infect Dis 2012; 18(6): 901– 907. doi: 10.3201/ eid1806.120116.

12. Head MW. Human prion diseases: molecular, cellular and population biology. Neuropathology 2013; 33(3): 221– 236. doi: 10.1111/ neup.12016.

13. Rohan Z, Parobkova E, Johanidesova S, Koukolik F, Matej R, Rusina R. Lidksé prionové nemoci v České republice – 10 let zkušeností s diagnostikou. Cesk Slov Neurol N 2013; 76/ 109(3): 300– 306.

14. Imran M, Mahmood S. An overview of human prion diseases. Virol J 2011; 8: 559. doi: 10.1186/ 1743‑ 422X‑ 8‑ 559.

15. O‘Connor T, Frei N, Sponarova J, Schwarz P, Heikenwalder M, Aguzzi A. Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes. PLoS Pathog 2012; 8(8): e1002867. doi: 10.1371/ journal.ppat.1002867.

16. Mabbott NA, Macpherson GG. Prions and their lethal journey to the brain. Nat Rev Microbiol 2006; 4(3): 201– 211.

17. Soto C, Satani N. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol Med 2011; 17(1): 14– 24. doi: 10.1016/ j.molmed.2010.09.001.

18. Prusiner SB. A unifying role for prions in neurodegenerative diseases. Science 2012; 336(6088): 1511– 1513. doi: 10.1126/ science.1222951.

19. Goedert M, Clavaguera F, Tolnay M. The propagation of prion‑like protein inclusions in neurodegenerative diseases. Trends Neurosci 2010; 33(7): 317– 325. doi: 10.1016/ j.tins.2010.04.003.

20. Schmidt C, Karch A, Korth C, Zerr I. On the issue of transmissibility of Alzheimer disease a critical review. Prion 2012; 6(5): 447– 452. doi: 10.4161/ pri.22502.

21. Prusiner SB. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 2013; 47: 601– 623. doi: 10.1146/ annurev‑ genet‑ 110711‑ 155524.

22. Ashe KH, Aguzzi A. Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion 2013; 7(1): 55– 59. doi: 10.4161/ pri.23061.

23. Westergard L, Christensen HM, Harris DA. The cellular prion protein (PrP(C)): its physiological function and role in disease. Biochim Biophys Acta 2007; 1772(6): 629– 644.

24. Yusa S, Oliveira‑ Martins JB, Sugita‑ Konishi Y, Kikuchi Y. Cellular prion protein: from physiology to pathology. Viruses 2012; 4(11): 3109– 3131. doi: 10.3390/ v4113109.

25. Choi CJ, Kanthasamy A, Anantharam V, Kanthasamy AG.Interaction of metals with prion protein: possible role of divalent cations in the pathogenesis of prion diseases. Neurotoxicology 2006; 27(5): 777– 787.

26. Holada K, Simak J, Risitano AM, Maciejewski J, Young NS,Vostal JG. Activated platelets of patients with paroxysmal nocturnal hemoglobinuria express cellular prion protein. Blood 2002; 100(1): 341– 343.

27. Knaus KJ, Morillas M, Swietnicki W, Malone M, Surewicz WK, Yee VC. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nat Struct Biol 2001; 8(9): 770– 774.

28. Zahn R, Liu AZ, Luhrs T, Riek R, Von Schroetter C, Garcia FL et al. NMR solution structure of the human prion protein. Proc Natl Acad Sci U S A 2000; 97(1): 145– 150.

29. Jeong BH, Kim YS. Genetic studies in human prion diseases. J Korean Med Sci 2014; 29(5): 623– 632. doi: 10.3346/ jkms.2014.29.5.623.

30. Mitrova E, Kosorinova D, Gajdos M, Sebekova K, Tomeckova I. A pilot study of a genetic CJD risk factor (E200K) in the general Slovak population. Eur J Epidemiol 2014; 29(8): 595– 597. doi: 10.1007/ s10654‑ 014‑ 9937‑ 9.

31. Taylor DR, Hooper NM. The prion protein and lipid rafts (review). Mol Membr Biol 2006; 23(1): 89– 99.

32. Kikuchi Y, Kakeya T, Nakajima O, Sakai A, Ikeda K, Yamaguchi N et al. Hypoxia induces expression of a GPI‑ anchorless splice variant of the prion protein. FEBS J 2008; 275(11): 2965– 2976. doi: 10.1111/ j.1742‑ 4658.2008.06452.x.

33. Liang JJ, Kong QZ. Alpha‑ cleavage of cellular prion protein. Prion 2012; 6(5): 453– 460. doi: 10.4161/ pri.22511.

34. Stahl N, Prusiner SB. Prions and prion proteins. FASEB J 1991; 5(13): 2799– 2807.

35. Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D et al. Conversion of alpha‑ helices into beta‑sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 1993; 90(23): 10962– 10966.

36. Safar J, Roller PP, Gajdusek DC, Gibbs CJ. Conformational transitions, dissociation and unfolding of scrapie amyloid (prion) protein. J Biol Chem 1993; 268(27): 20276– 20284.

37. Aguzzi A, Heikenwalder M, Polymenidou M. Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 2007; 8(7): 552– 561.

38. Bendheim PE, Bolton DC. A 54- kDa normal cellular protein may be the precursor of the scrapie agent protease‑resistant protein. Proc Natl Acad Sci U S A 1986; 83(7): 2214– 2218.

39. Grassi J, Maillet S, Simon S, Morel N. Progress and limits of TSE diagnostic tools. Vet Res 2008; 39(4): 33. doi: 10.1051/ vetres:2008009.

40. Dvořáková E, Holada K. Konformačně specifické protilátky a diagnostika prionových chorob. Cesk Slov Neurol N 2012; 75/ 108(3): 283– 290.

41. Sakudo A, Ano Y, Onodera T, Nitta K, Shintani H, Ikuta K et al. Fundamentals of prions and their inactivation (review). Int J Mol Med 2011; 27(4): 483– 489. doi: 10.3892/ ijmm.2011.605.

42. Manson J, West JD, Thomson V, Mcbride P, Kaufman MH,Hope J. The prion protein gene: a role in mouse embryogenesis. Development 1992; 115(1): 117– 122.

43. Ford MJ, Burton LJ, Morris RJ, Hall SM. Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience 2002; 113(1): 177– 192.

44. Vostal JG, Holada K, Simak J. Expression of cellular prion protein on blood cells: Potential functions in cell physiology and pathophysiology of transmissible spongiform encephalopathy diseases. Transfus Med Rev 2001; 15(4): 268– 281.

45. Nitta K, Sakudo A, Masuyama J, Xue GG, Sugiura K, Onodera T. Role of cellular prion proteins in the function of macrophages and dendritic cells. Protein Pept Lett 2009; 16(3): 239– 246.

46. Brouckova A, Holada K. Cellular prion protein in blood platelets associates with both lipid rafts and the cytoskeleton. Thromb Haemost 2009; 102(5): 966– 974. doi: 10.1160/ TH09‑ 02‑ 0074.

47. Didonna A. Prion protein and its role in signal transduction. Cell Mol Biol Lett 2013; 18(2): 209– 230. doi: 10.2478/ s11658‑ 013‑ 0085‑ 0.

48. Gunther EC, Strittmatter SM. Beta‑amyloid oligomers and cellular prion protein in Alzheimer‘s disease. J Mol Med (Berl) 2010; 88(4): 331– 338. doi: 10.1007/ s00109‑ 009‑ 0568‑ 7.

49. Aguzzi A, Baumann F, Bremer J. The prion‘s elusive reason for being. Annu Rev Neurosci 2008; 31: 439– 477. doi: 10.1146/ annurev.neuro.31.060407.125620.

50. Roucou X, Leblanc AC. Cellular prion protein neuroprotective function: implications in prion diseases. J Mol Med (Berl) 2005; 83(1): 3– 11.

51. Zanata SM, Lopes MH, Mercadante AF, Hajj GNM, Chiarini LB, Nomizo R et al. Stress‑ inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J 2002; 21(13): 3307– 3316.

52. Brown DR, Schmidt B, Kretzschmar HA. Effects of copper on survival of prion protein knockout neurons and glia. J Neurochem 1998; 70(4): 1686– 1693.

53. Brown DR, Schulz‑ Schaeffer WJ, Schmidt B, Kretzschmar HA. Prion protein‑deficient cells show altered response to oxidative stress due to decreased SOD‑ 1 activity. Exp Neurol 1997; 146(1): 104– 112.

54. Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA. Hippocampal synaptic plasticity in mice devoid of cellular prion protein. Brain Res Mol Brain Res 2004; 131(1– 2): 58– 64.

55. Coitinho AS, Freitas ARO, Lopes MH, Hajj GN, Roesler R, Walz R et al. The interaction between prion protein and laminin modulates memory consolidation. Eur J Neurosci 2006; 24(11): 3255– 3264.

56. Hobzova K, Janouskova O. Tkáňové kultury pro studium prionových chorob. Cesk Slov Neurol N 2010; 73/ 106(4): 379– 386.

57. Steele AD, Lindquist S, Aguzzi A. The prion protein knockout mouse: a phenotype under challenge. Prion 2007; 1(2): 83– 93.

58. Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M et al. Mice devoid of PrP are resistant to scrapie. Cell 1993; 73(7): 1339– 1347.

59. Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, Dearmond SJ et al. Normal development and behavior of mice lacking the neuronal cell‑ surface PrP protein. Nature 1992; 356(6370): 577– 582.

60. Tremblay P, Bouzamondo‑ Bernstein E, Heinrich C, Prusiner SB, Dearmond SJ. Developmental expression of PrP in the post‑implantation embryo. Brain Res 2007; 1139: 60– 67.

61. Hajj GN, Santos TG, Cook ZS, Martins VR. Developmental expression of prion protein and its ligands stress‑ inducible protein 1 and vitronectin. J Comp Neurol 2009; 517(3): 371– 384. doi: 10.1002/ cne.22157.

62. Peralta OA, Huckle WR, Eyestone WH. Developmental expression of the cellular prion protein (PrP(C)) in bovine embryos. Mol Reprod Dev 2012; 79(7): 488– 498. doi: 10.1002/ mrd.22057.

63. Peralta OA, Huckle WR, Eyestone WH. Expression and knockdown of cellular prion protein (PrPC) in differentiating mouse embryonic stem cells. Differentiation 2011; 81(1): 68– 77. doi: 10.1016/ j.diff.2010.09.181.

64. Miranda A, Pericuesta E, Angel Ramirez M, Gutierrez‑ Adan A. Prion protein expression regulates embryonic stem cell pluripotency and differentiation. PLoS ONE 2011; 6(4): e18422. doi: 10.1371/ journal.pone.0018422.

65. Lee YJ, Baskakov IV. Treatment with normal prion protein delays differentiation and helps to maintain high proliferation activity in human embryonic stem cells. J Neurochem 2010; 114(2): 362– 373. doi: 10.1111/ j.1471‑ 4159.2010.06601.x.

66. Lee YJ, Baskakov IV. The cellular form of the prion protein is involved in controlling cell cycle dynamics, self‑ renewal, and the fate of human embryonic stem cell differentiation. J Neurochem 2013; 124(3): 310– 322. doi: 10.1111/ j.1471‑ 4159.2012.07913.x.

67. Adle‑ Biassette H, Verney C, Peoc‘h K, Dauge MC, Razavi F,Choudat L et al. Immunohistochemical expression of prion protein (PrPC) in the human forebrain during development. J Neuropathol Exp Neurol 2006; 65(7): 698– 706.

68. Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci U S A 2006; 103(9): 3416– 3421.

69. Gage FH. Mammalian neural stem cells. Science 2000; 287(5457): 1433– 1438.

70. Witusik M, Gresner SM, Hulas‑ Bigoszewska K, Krynska B,Azizi SA, Liberski PP et al. Neuronal and astrocytic cells, obtained after differentiation of human neural GFAP‑ positive progenitors, present heterogeneous expression of PrPc. Brain Res 2007; 1186: 65– 73.

71. Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 2008; 11(8): 901– 907. doi: 10.1038/ nn.2156.

72. Peretto P, Giachino C, Aimar P, Fasolo A, Bonfanti L. Chain formation and glial tube assembly in the shift from neonatal to adult subventricular zone of the rodent forebrain. J Comp Neurol 2005; 487(4): 407– 427.

73. Relano‑ Gines A, Gabelle A, Hamela C, Belondrade M,Casanova D, Mourton‑ Gilles C et al. Prion replication occurs in endogenous adult neural stem cells and alters their neuronal fate: Involvement of endogenous neural stem cells in prion diseases. PLoS Pathog 2013; 9(8): e1003485.

74. Peng HM, Chen G. Neural precursors derived from human embryonic stem cells. Sci China C Life Sci 2005; 48(3): 295– 299.

75. Kanaani J, Prusiner SB, Diacovo J, Baekkeskov S, Legname G. Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro. J Neurochem 2005; 95(5): 1373– 1386.

76. Bribian A, Fontana X, Llorens F, Gavin R, Reina M, Manuel Garcia‑ Verdugo J et al. Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS. PLoS ONE 2012; 7(4): e33872. doi: 10.1371/ journal.pone.0033872.

77. Hartmann CA, Martins VR, Souza Lima FR. High levels of cellular prion protein improve astrocyte development. FEBS Lett 2013; 587(2): 238– 244. doi: 10.1016/ j.febslet.2012.11.032.

78. Kovacs GG, Preusser M, Strohschneider M, Budka H.Subcellular localization of disease‑associated prion protein in the human brain. Am J Pathol 2005; 166(1): 287– 294.

79. Ferrer I. Synaptic pathology and cell death in the cerebellum in Creuzfeldt‑ Jakob disease. Cerebellum 2002; 1(3): 213– 222.

80. Faustino RS, Behfar A, Perez‑ Terzic C, Terzic A. Genomic chart guiding embryonic stem cell cardiopoiesis. Genome Biol 2008; 9(1): R6. doi: 10.1186/ gb‑ 2008‑ 9‑ 1‑ r6.

81. Hidaka K, Shirai M, Lee J‑ K, Wakayama T, Kodama I, Schneider MD et al. The cellular prion protein identifies bipotential cardiomyogenic progenitors. Circ Res 2010; 106(1): 111– 119.

82. Massimino ML, Ferrari J, Sorgato MC, Bertoli A. Heterogeneous PrPC metabolism in skeletal muscle cells. FEBS Lett 2006; 580(3): 878– 884.

83. Stella R, Massimino ML, Sandri M, Sorgato MC, Bertoli A.Cellular prion protein promotes regeneration of adult muscle tissue. Mol Cell Biol 2010; 30(20): 4864– 4876. doi: 10.1128/ MCB.01040‑ 09.

84. Holada K, Vostal JG. Different levels of prion protein (PrPc) expression on hamster, mouse and human blood cells. Br J Haematol 2000; 110(2): 472– 480.

85. Holada K, Simak J, Brown P, Vostal JG. Divergent expression of cellular prion protein on blood cells of human and nonhuman primates. Transfusion 2007; 47(12): 2223– 2232.

86. Holada K, Simak J, Vostal JG. Transmission of BSE by blood transfusion. Lancet 2000; 356(9243): 1772.

87. Lin T, Li RL, Wong BS, Liu DC, Pan T, Petersen RB et al. Normal cellular prior protein is preferentially expressed on subpopulations of murine hemopoietic cells. J Immunol 2001; 166(6): 3733– 3742.

88. Dodelet VC, Cashman NR. Prion protein expression in human leukocyte differentiation. Blood 1998; 91(5): 1556– 1561.

89. Panigaj M, Glier H, Wildova M, Holada K. Expression of prion protein in mouse erythroid progenitors and differentiating murine erythroleukemia cells. PLoS ONE 2011; 6(9): e24599. doi: 10.1371/ journal.pone.0024599.

90. Panigaj M, Brouckova A, Glierova H, Dvorakova E, Simak J, Vostal JG et al. Underestimation of the expression of cellular prion protein on human red blood cells. Transfusion 2011; 51(5): 1012– 1021. doi: 10.1111/ j.1537‑ 2995.2010.02924.x.

91. Zhang CC, Steele AD, Lindquist S, Lodish HF. Prion protein is expressed on long‑term repopulating hematopoietic stem cells and is important for their self‑ renewal. Proc Natl Acad Sci U S A 2006; 103(7): 2184– 2189.