Skip to main content
SpringerLink
Log in
Book cover

Neurodegeneration and Prion Disease pp 299–318Cite as

Processing and Mis-Processing of the Prion Protein: Insights into the Pathogenesis of Familial Prion Disorders

  • Chapter

12.1. Summary

The cellular prion protein (PrPC), though apparently innocuous, is the main agent responsible for infectious, familial, and sporadic prion disorders. Through its remarkable ability to undergo a change in conformation from a mainly α-helical to a β-sheet rich conformation commonly referred to as PrP-scrapie (PrPSc), PrPC becomes infectious and pathogenic, a feature that is unique to this glycoprotein1–4. Over the years, most studies have focused on the mechanism of PrPC to PrPSc conversion and its subsequent transmission to susceptible hosts, ignoring the less common familial prion disorders that result from point mutations in the prion protein gene (PRNP). In these disorders, mutant PrP (PrPM) is presumed to undergo a spontaneous change in conformation to PrPSc without participation from an exogenous source of in-fectious PrPSc. Once initiated, the process proceeds exponentially, and deposits of mutant PrPSc are believed to result in the neurotoxicity ob-served in familial cases of prion disorders5,6. However, prion-specific neuropathology is often observed in the absence of detectable PrPSc, indicating the presence of alternative pathways of neurotoxicity incertain cases of prion disorders7. Recent studies on the processing of normal and mutant PrP underscore the importance of abnormal metabolism and various topological forms of PrP in prion disease pathogenesis8. In this chapter, we will review information on the complex pathways of intracellular trafficking and metabolism of normal and various mutant PrP forms, and highlight some of the abnormal pathways that may contribute to neurotoxicity in familial prion disorders.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. S. B. Prusiner, Molecular Biology and Genetics of Prion Diseases. In Cold Spring Harbor Symposia on Quantitative Biology LXI, Cold Spring Harbor Laboratory Press, (1996) pp. 473–493.

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. S. B. Prusiner, M. R. Scott, S. J. DeArmond, and F. E. Cohen, Prion protein biology. Cell 93, 337–348 (1998).

    Article  PubMed  Google Scholar 

  4. A. L. Horwich, and J. S. Weissman, Deadly conformations-Protein misfolding in Prion disease. Cell 89, 495–510 (1997).

    Article  PubMed  Google Scholar 

  5. S. B. Prusiner, Inherited prion diseases. Proc Natl. Acad. Sci. U.S.A. 91, 4611–4614 (1994).

    PubMed  Google Scholar 

  6. J. Collinge, Prion diseases of humans and animals: Their causes and molecular basis. Annu. Rev. Neurosci. 24, 519–550 (2001).

    Article  PubMed  Google Scholar 

  7. R. Chiesa, and D. Harris, Prion diseases: What is the neurotoxic molecule? Neurobiol.Dis. 8, 743–763 (2001).

    PubMed  Google Scholar 

  8. D. Harris, Trafficking, turnover and membrane topology of PrP. British Medical Bulletin 66, 71–85 (2003).

    PubMed  Google Scholar 

  9. K. K. Hsiao, M. M. Scott, D. Foster, D. F. Groth, S. J. Groth, S. J. DeArmond, and S. B. Prusiner, Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250, 1587–1590 (1990).

    PubMed  Google Scholar 

  10. C. I. Lasmezas, J. P. Deslys, O. Robain, A. Jaegly V. Beringue, J. M. Peyrin, J. G. Fournier, J. J. Hauw, J. Rossier, and D. Dormont, Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275, 402–5 (1997).

    PubMed  Google Scholar 

  11. R. S. Hegde, J. A. Mastrianni, M. R. Scott, K. A. DeFea, P. Tremblay M. Torchia, S. J. DeArmond, S. B. Prusiner, and V. R. Lingappa, A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).

    PubMed  Google Scholar 

  12. R. S. Hegde, P. Trembly, D. Groth, S. J. DeArmond. S. B. Prusiner, and V. R. Lingappa, Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826 (1999).

    PubMed  Google Scholar 

  13. J. Ma, and S. Lindquist, De novo generation of a PrPSc-like conformation in living cells. Nature Cell Boil. 1, 358–361 (1999).

    Google Scholar 

  14. J. Ma, and S. Lindquist, Wild type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. Proc. Natl. Acad. Sci. U.S.A. 98, 14955–60 (2001).

    PubMed  Google Scholar 

  15. J. Ma, and S. Lindquist, Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298, 1785–1788 (2002).

    PubMed  Google Scholar 

  16. J. Ma, R. Wollmann, and S. Lindquist, Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298, 1781–1785 (2002).

    PubMed  Google Scholar 

  17. T. Kitamoto, R. lizuka, and J. Tateishi, An amber mutation of prion protein in Gerstmann-Sträussler-Scheinker syndrome with mutant PrP plaques. Biochem. Biophys. Res. Comm. 192, 525–531 (1993).

    PubMed  Google Scholar 

  18. B. Drisaldi, R. S. Stewart, C. Adles, L. R. Stewart, E. Quaglio, E. Biasini, L. Fioriti, R. Chiesa, and D. A. Harris, Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation. J Biol Chem. 278, 21732–13 (2003).

    PubMed  Google Scholar 

  19. C. Hammond, and A. Helenius, Quality control in the secretory pathway. Curr. Opin. Cell Biol. 7, 523–529 (1995).

    PubMed  Google Scholar 

  20. X. Roucou, Q. Guo, Y. Zhang, C. Goodyer, and A. LeBlanc, Cytosolic prion protein is not toxic and protects against Bax-mediated cell death in human primary neurons. J. Biol. Chem. 278, 40877–40881 (2003).

    Google Scholar 

  21. Y. Yedidia, L. Horonchik, S. Tzaban, A. Yanai, and A. Taraboulos, Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein. EMBO J. 20, 5383–5391 (2001).

    PubMed  Google Scholar 

  22. R. S. Mishra, S. Bose, Y. Gu, R. Li, and N. Singh, Aggresome formation by mutant prion proteins: the unfolding role of proteasomes in familial prion disorders. J. Alzheimers Dis. 5, 15–23. (2002).

    Google Scholar 

  23. G. Mallucci, A. Dickinson, J. Linehan, P. C. Klohn, S. Brandner, and J. Collinge, Depleting neuronal PrP in prion infection prevents diseaseand reverses spongiosis. Science 302, 871–1 (2003).

    Article  PubMed  Google Scholar 

  24. M. Jeffrey, C. M. Goodsir, R. E. Race, and B. Chesebro, Scrapie-specific neuronal lesionsare independentof neuronal PrP expression. Ann Neurol. 55, 781–92 (2004).

    PubMed  Google Scholar 

  25. A. J. Raeber, R. E. Race, S. Brandner, S. A. Priola, A. Sailer, R. A. Bessen, L. Mucke, J. Manson, A. Aguzzi, M. B. Oldstone, C. Weissmann, and B. Chesebro, Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J. 16, 6057–65 (1997).

    PubMed  Google Scholar 

  26. M. Marella, and J. Chabry, Neurons and astrocytes respond to prion infection by inducing microglia recruitment. J. Neurosci. 24, 620–7 (2004).

    PubMed  Google Scholar 

  27. N. Stahl, M. A. Baldwin, R. Hecker, K. M. Pan, A. L. Burlingame, and S. B. Prusiner, Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid. Biochemistry 31, 5043–53 (1992).

    PubMed  Google Scholar 

  28. B. Caughey, R. E. Race, D. Ernst, M. J. Buchmeier, and B. Chesebro, Prion protein biosynthesis in scrapie-infected and uninfected neuroblastoma cells. J. Virol. 63, 175–181 (1989).

    PubMed  Google Scholar 

  29. S. L. Shyng, M. T. Huber, and D. A. Harris, A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells. J. Biol. Chem. 268, 15922–8 (1993).

    PubMed  Google Scholar 

  30. M. Muniz, and H. Riezman, Intracellular transport of GPI-anchored proteins. EMBO J. 19, 10–15 (2000).

    PubMed  Google Scholar 

  31. S. Udenfriend, and K. Kodukula, How glycosyl-phosphatidylinositol-anchored membrane proteins are made. Ann. Rev. Biochem. 64, 563–591 (1995).

    PubMed  Google Scholar 

  32. A. Taraboulos, M. Scott, A. Semenov, D. Avrahami, L. Laszlo, and S. B. Prusiner, Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform. J. Cell Biol. 129, 121–32 (1995).

    PubMed  Google Scholar 

  33. S. G. Chen, D. B. Teplow, R. Parchi, J. K. Teller, P. Gambetti, and L. Autilio-Gambetti. Truncated forms of the human prion protein in normal brain and in prion diseases. J. Biol. Chem 270, 19173–19180 (1995).

    PubMed  Google Scholar 

  34. S. L. Shyng, J. E. Heuser, and D. A. Harris, A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits. J. Cell. Biol. 125, 1239–50 (1994).

    PubMed  Google Scholar 

  35. S. L. Shyng, K. L. Moulder, A. Lesko, and D. A. Harris. The N-terminal domain of a glycolipid-anchored prion protein is essential for its endocytosis via clathrin-coated pits. J. Biol. Chem. 270, 14793–800 (1995).

    PubMed  Google Scholar 

  36. P. C. Pauly, and D. A. Harris, Copper stimulates endocytosis of the prion protein. J. Biol. Chem. 273, 33107–10 (1998).

    PubMed  Google Scholar 

  37. S. L. Shyng, S. Lehmann, K. L. Moulder, and D. A. Harris. Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells. J. Biol. Chem. 270, 30221–29 (1995).

    PubMed  Google Scholar 

  38. R. S. Stewart, and D. A. Harris, Most pathogenic mutations do not alter the membrane topology of the prion protein. J. Biol. Chem. 276, 2212–20 (2001).

    PubMed  Google Scholar 

  39. R. S. Stewart, B. Drisaldi, and D. A. Harris, A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic Reticulum. Mol. Biol. Cell 12, 881–889 (2001).

    PubMed  Google Scholar 

  40. Y. Gu, H. Fujioka, R. S. Mishra, R. Li, and N. Singh, Prion peptide 106–126 modulates the aggregation of cellular prion protein and induces the synthesis of potentially neurotoxic transmembrane PrP J. Biol. Chem. 277, 2275–2286 (2002).

    PubMed  Google Scholar 

  41. R. S. Mishra, Y. Gu, S. Bose, S. Verghese, S. Kalepu, and N. Singh, Cell surface accumulation of a truncated transmembrane prion protein in Gerstmann-Straussler-Scheinker disease P102L. J. Biol. Chem. 277, 24554–61 (2002).

    PubMed  Google Scholar 

  42. L. Ellgaard, M. Molinari, A. Helenius, Setting the standards: quality control in the secretory pathway. Science 286, 1882–8 (1999).

    Article  PubMed  Google Scholar 

  43. J. L. Brodsky and A. A. McCracken, ER-associated and proteasome-mediated protein degradation: how two topologically restricted events came together. TICB 7, 151–156 (1997).

    Google Scholar 

  44. S. Capellari, S. I. A. Zaidi, A. C. Long, E. E. Kwon, and R. B. Petersen, The Thr183A mutation, not the loss of the first glycosylation site, alters the physical properties of the prion protein. J. Alzheimers Dis 2, 27–35 (2000).

    PubMed  Google Scholar 

  45. S. Capellari, P. Parchi, C. M. Russo, J. Sanford, M. S. Sy, P. Gambetti, and R. B. Petersen, Effect of the E200K mutation on prion protein metabolism. Am. J. Pathol 157, 613–22 (2000).

    PubMed  Google Scholar 

  46. S. Lehmann, and D. A. Harris, Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform. Proc. Natl. Acad. Sci. USA 93, 5610–5614 (1996).

    PubMed  Google Scholar 

  47. S. Lehmann, and D. A. Harris, Mutant and infectious prion proteins display common biochemical properties in cultured cells. J. Biol. Chem. 271, 1633–1637 (1996).

    PubMed  Google Scholar 

  48. M. D. Delahunty, F. J. Stafford, L. C. Yuan, D. Shaz, J. S. Bonifacino, Uncleaved Signals for Glycosylphosphatidylinositol Anchoring Cause Retention of Precursor Proteins in the Endoplasmic Reticulum. J. Biol. Chem. 268, 12017–12027 (1993).

    PubMed  Google Scholar 

  49. M. C. Field, P. Moran, W. Li, G. Keller, I. W. Caras, Retention and Degradation of Proteins Containing an Uncleaved Glycosylphosphatidylinositol Signal. J. Biol. Chem. 269, 10830–10837 (1994).

    PubMed  Google Scholar 

  50. D. A. Kocisko, J. H. Come, S. A. Priola, B. Chesebro, G. J. Raymond, P. T. Lansbury, and B. Caughey, Cell-free formation of protease-resistant prion protein. Nature 370, 471–1 (1994).

    PubMed  Google Scholar 

  51. T. Jin, Y. Gu, G. Zanusso, M. Sy, A. Kumar, M. Cohen, P. Gambetti, and N. Singh, The chaperone protein BiP binds to a mutant prion protein and mediates its degradation by the proteasome. J Biol Chem. 275, 38699–704 (2000).

    PubMed  Google Scholar 

  52. Gu, Y., Verghese, S., Mishra, R.S., Xu, X., Shi, Y., and Singh, N. (2003) Mutant prion protein (PrP) mediated aggregation of normal PrP in the endoplasmic reticulum: Implications for prion propagation and neurotoxicity. J. Neurochem. 84, 10–22.

    PubMed  Google Scholar 

  53. G. Zanusso, R. B. Petersen, T. Jin, Y. Jing, R. Kanoush, S. Ferrari, P. Gambetti, and N. Singh, Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein. J. Biol. Chem. 274, 23396–404 (1999).

    PubMed  Google Scholar 

  54. H. Lorenz, O. Windl, and H. A. Kretzschmar, Cellular phenotyping of secretory and nuclear prion proteins associated with inherited prion diseases. J. Biol. Chem. 277, 8508–16 (2002).

    PubMed  Google Scholar 

  55. N. Singh, G. Zanusso, S. G. Chen, H. Fujioka, S. Richardson, P. Gambetti, and R. B. Petersen, Prion protein aggregation reverted by low temperature in transfected cells carrying a prion protein gene mutation. J. Biol. Chem. 272, 28461–70 (1997).

    PubMed  Google Scholar 

  56. F. Tagliavini, F. Prelli, J. Ghiso, O. Bugiani, D. Serban, S. B. Prusiner, M. R. Farlow, B. Ghetti, and B. Frangione, Amyloid protein of Gertsmann-Straussler-Schinker disease (Indiana Kindred) is an 11kd fragment of prion protein with an N-terminal glycine at codon 58. EMBO. J. 10, 513–519 (1991).

    PubMed  Google Scholar 

  57. P. Piccardo, B. Ghetti, D. W. Dickson, H. V. Vinters, G. Giaccone, O. Bugiani, F. Tagliavini, K. Young, S. R. Dlouhy, and C. Seiler, Gertsmann-Straussler-Scheinker disease (PRNP P102L): amyloid deposits are best recognised by antibodies directed toepitopes in PrP region 90–165. J. Neuropathol. Exp. Neurol. 54, 790–801 (1995).

    PubMed  Google Scholar 

  58. B. Ghetti, P. Piccardo, M. G. Spillantini, Y. Ichimiya, M. Porro, F. Perini, T. Kitamoto, J. Tateishi, C. Seiler, B. Frangione, O. Bugiani, G. Giaccone, F. Prelli, M. Goedert, S. R. Dlouhy, and F. Tagliavini, Vascular variant of prion protein cerebral amyloidosis with Tau-positive neurofibrillary tangles: The phenotype of the stop codon 145 mutation in PRNR. Proc. Natl. Acad. Sci. USA. 93, 744–748 (1996).

    PubMed  Google Scholar 

  59. R. Gabizon, G. Telling, Z. Meiner, M. Halimi, I. Kahana, and S. B. Prusiner, Insoluble wild type and protease-resistant mutant prion protein in brains of patients with inherited prion disease. Nat. Med. 2, 59–64 (1996).

    PubMed  Google Scholar 

  60. S. G. Chen, P. Parchi, P. Brown, S. Capellari, W. Zou, E. J. Cochran, C. L. Vnencak-Jones, J. Julien, C. Vital, J. Mikol, E. Lugaresi, L. Autilio-Gambetti, and P. Gambetti, Allelic origin of the abnormal prion protein isoform in familial prion diseases. Nat. Med. 3, 1009–1015 (1997).

    PubMed  Google Scholar 

  61. M. C. Silvestrini, F. Cardone, B. Maras, P. Pucci, D. Barra, M. Brunori, and M. Pocchiari, Identification of the prion protein allotypes which accumulate in the brain of sporadic and familial Creutzfeldt-Jakob disease patients. Nat. Med. 5, 521–5 (1997).

    Google Scholar 

  62. Y. Gu, J. Hinnerwisch, R. Fredricks, S. Kalepu, R. S. Mishra, and N. Singh, Identification of cryptic nuclear localization signals in the prion protein. Neurobiol. Dis. 12, 133–149 (2002).

    Google Scholar 

  63. A. Jimenez-Huete, P. M. Lievens, R. Vidal, P. Piccardo, B. Ghetti, F. Tagliavini, B. Frangione, F. Prelli, Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. Am. J Pathol. 153, 1561–72 (1998).

    PubMed  Google Scholar 

  64. H. E. McMahon, A. Mange, N. Nishida, C. Creminon, D. Casanova, and S. Lehmann, Cleavage of the amino-terminus of the prion protein by reactive oxygen species. J. Biol. Chem. 276, 2286–2291 (2000).

    PubMed  Google Scholar 

  65. Y. Gu, and N. Singh, Doxycycline and protein folding agents rescue the abnormal phenotype of CJD H187R in a cell model. Brain Res Mol Brain Res. 123, 37–44. (2004).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Neena Singh, Yaping Gu, Subhabrata Basu, Xiu Luo, Richa Mishra & Oscar Kuruvilla

  2. Department of Molecubr, Cellular and Developmental Biology, The University of Michigan, MI, USA

    Sharmila Bose

Authors
  1. Neena Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yaping Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sharmila Bose
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Subhabrata Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiu Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richa Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oscar Kuruvilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Bath, UK

    David R. Brown

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Singh, N. et al. (2005). Processing and Mis-Processing of the Prion Protein: Insights into the Pathogenesis of Familial Prion Disorders. In: Brown, D.R. (eds) Neurodegeneration and Prion Disease. Springer, Boston, MA. https://doi.org/10.1007/0-387-23923-5_12

Download citation

Publish with us

Policies and ethics

Search

Navigation