Prion Diseases and Dementia

  • Piero Parchi
  • Pierluigi Gambetti
Part of the Contemporary Neuroscience book series (CNEURO)


Prion diseases are a group of neurodegenerative conditions of humans and animals that include sporadic, inherited, and transmitted forms. They are best characterized by their distinctive pathogenic mechanism, which is shared by all three forms. The central event in the pathogenesis of these diseases is thought to be a change in protein conformation that results in the conversion of a normal protein, identified as cellular prion protein (PrPC), into an isoform that is partially resistant to proteases (PrPres) (1). The molecular events leading to this conformational change, however, remain largely unknown.


Prion Protein Prion Disease Progressive Dementia Fatal Familial Insomnia Human Prion Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Prusiner, S. B. and DeArmond, S. J. (1994) Prion diseases and neurodegeneration, Ann. Rev. Neurosci. 17, 311–319.PubMedCrossRefGoogle Scholar
  2. 2.
    Parchi, P. and Gambetti, P. (1995) Human prion diseases, Curr. Opinion Neurol. 8, 286–293.CrossRefGoogle Scholar
  3. 3.
    Fraser, H. and Dickinson, A. G. (1973) Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation, J. Comp. Pathol. 83, 23–40.CrossRefGoogle Scholar
  4. 4.
    Hecker, R., Taraboulos, A., Scott, M., Pan, K. M., Yang, S. L., Torchia, M., Jendroska, K., DeArmond, S. J., and Prusiner, S. B. (1992) Replication of distinct scrapie prion isolates is region specific in brains of transgenic mice and hamsters, Genes Dey. 6, 1213–1228.CrossRefGoogle Scholar
  5. 5.
    Brown, P., Gibbs, C. J., Rodgers-Johnson, P., Asher, D. M., Sulima, M. P., Bacote, A., Goldfarb, L. G., and Gajdusek, D. C. (1994) Human spongiform encephalopathy: The National Institutes of Health series of 300 cases of experimentally transmitted disease, Ann. Neurol. 35, 513–529.PubMedCrossRefGoogle Scholar
  6. 6.
    Parchi, P., Castellani, R., Capellari, S., Ghetti, B., Young, K., Chen, S. G., Farlow, M., Dickson, D. W., Sima, A. A. F., Trojanowski, J. Q., Petersen, R. B., and Gambetti, R (1996) Molecular basis of phenotypic variability in sporadic Creutzfelt-Jakob disease, Ann. Neurol. 39, 767–778.PubMedCrossRefGoogle Scholar
  7. 7.
    Richardson, E. P. and Masters, C. L. (1995) The nosology of Creutzfeldt-Jakob disease and conditions related to the accumulation of PrPcm in the nervous system, Brain Pathol. 5, 33–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Brown, P., Goldfarb, L. G., Kovanen, J., Haltia, M., Cathala, F., Sulima, M., Gibbs, C. J., and Gajdusek, D. C. (1992) Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178 Asn PRNP mutation, Ann. Neurol. 31, 282–285.PubMedCrossRefGoogle Scholar
  9. 9.
    Bertoni, J. M., Brown, P., Goldfarb, L. G., Rubenstein, R., and Gajdusek, D. C. (1992) Familial Creutzfeldt-Jakob disease (codon 200 mutation) with supranuclear palsy, JAMA 268, 2413–2415.PubMedCrossRefGoogle Scholar
  10. 10.
    Tietjen, G. E. and Drury, I. (1990) Familial Creutzfeldt-Jakob disease without periodic EEG activity, Ann. Neurol. 28, 585–588.PubMedCrossRefGoogle Scholar
  11. 11.
    Pocchiari, M., Salvatore, M., Cutruzzola, F., Genuardi, M., Allocatelli, C. T., Masullo, C., Macchi, G., Alema, G., Galgani, S., Xi, Y. G., Petraroli, R., Silvestrini, M. C., and Brunori, M. (1993) A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease, Ann. Neurol. 34, 802–807.PubMedCrossRefGoogle Scholar
  12. 12.
    Kitamoto, T. and Tateishi, J. (1994) Human prion diseases with variant prion protein, Phil. Trans. R. Soc. Lond. B. 343, 391–398.CrossRefGoogle Scholar
  13. 13.
    Goldfarb, L. G., Petersen, R. B., Tabaton, M., Brown, P., LeBlanc, A. C., Montagna, P., Cortelli, P., Julien, J., Vital, C., Pendlebury, W. W., Haltia, M., Willis, P. R., Hauw, J. J., McKeever, P. E., Monari, L., Schrank, B., Swergold, G. D., Autilio-Gambetti, L., Gajdusek, C., Lugaresi, E., and Gambetti, P. (1992) Fatal familial insomnia and Familial Creutzfeldt Jakob disease: disease phenotype determined by a DNA polymorphism, Science 258, 806–808.PubMedCrossRefGoogle Scholar
  14. 14.
    Parchi, P., Castellani, R., Cortelli, P., Montagna, P., Chen, S. G., Petersen, R. B., Manetto, V., Vnencak-Jones, C. L., McLean, M. J., Sheller, J. R., Lugaresi, E., Autilio-Gambetti, L., and Gambetti, P. (1995) Regional distribution of protease-resistant prion protein in Fatal Familial Insomnia, Ann Neurol. 38, 21–29.PubMedCrossRefGoogle Scholar
  15. 15.
    Perani, D., Cortelli, P., Lucignani, G., Montagna, P., Tinuper, R, Gallassi, R., Gambetti, R, Lenzi, G. L., Lugaresi, E., and Fazio, F. (1993) [18F] FDG PET in Fatal familial insomnia: the functional effects of thalamic lesions, Neurology 43, 2565–2569.Google Scholar
  16. 16.
    Perani, D., Parchi, P., Cortelli, P., Montagna, P., Grassi, F., Castellani, R., Gambetti, P., Lugaresi, E., and Fazio, F. (1995) Relationship between protease-resistant prion protein distribution and in vivo regional cerebral metabolism in Fatal Familial Insomnia (FFI), Neurology 45, A406.CrossRefGoogle Scholar
  17. 17.
    Gallassi, R., Morreale, A., Gambetti, P., and Lugaresi, E. (1992) Fatal familial insomnia: neuropsychological study of a disease with thalamic degeneration, Cortex 28, 175–187.PubMedGoogle Scholar
  18. 18.
    Gallassi, R., Morreale, A., Montagna, P., Cortelli, P., Avoni, P., Castellani, R., Gambetti, P., and Lugaresi, L. (1996) Fatal familial insomnia: behavioral and cognitive features, Neurology 46, 935–939.PubMedCrossRefGoogle Scholar
  19. 19.
    Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A., Cortelli, P., Lugaresi, A., Tinuper, R, Zucconi, M., and Gambetti, R (1986) Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei, N. Engl. J. Med. 315, 997–1003.PubMedCrossRefGoogle Scholar
  20. 20.
    Montagna, R, Cortelli, P., Tinuper, P., Sforza, E., Avoni, R, Gallassi, R., Morreale, A., Roiter, I., Perani, D., Lucignani, G., Fazio, F., and Lugaresi, E. (1994) Fatal familial insomnia: A disease that emphasizes the role of the thalamus in the regulation of sleep and vegetative functions, in Fatal Familial Insomnia: Inherited Prion Diseases, Sleep, and the Thalamus ( Guilleminault, C., Lugaresi, E., Montagna, P., and Gambetti, P., eds.), Raven, New York, pp. 1–14.Google Scholar
  21. 21.
    Tinuper, P., Montagna, P., Medori, R., Cortelli, P., Zucconi, M., Baruzzi, A., and Lugaresi, E. (1989) The thalamus participates in the regulation of the sleep-waking cycle. A clinicopathological study in Fatal Familial Thalamic degeneration, Electroencephalogic Clin. Neurophysiol. 73, 117–120.CrossRefGoogle Scholar
  22. 22.
    Ghetti, B., Dlouhy, S. R., Giaccone, G., Bugiani, O., Frangione, B., Farlow, M. R., and Tagliavini, F. (1995) Gerstmann-Sträussler-Scheinker disease and the Indiana kindred, Brain Pathol. 5, 61–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Ghetti, B., Piccardo, P., Spillantini, M. G., Ichimiya, Y., Porro, M., Perini, F., Kitamoto, T., Tateishi, J., Seiler, C., Frangione, B., Bugiani, O., Giaconne, G., Prelli, F., Goedert, M., Dlouhy, S. R., and Tagliavini, F. (1996) Vascular variant of prion protein cerebral amyloidosis with i-positive neurofibrillary tangles: The phenotype of the stop codon 145 mutation in PRNP, Proc. Natl. Acad. Sci. USA 93, 744–748.PubMedCrossRefGoogle Scholar
  24. 24.
    Dlouhy, S. R., Hsiao, K., Farlow, M. R., Foroud, T., Conneally, P. M., Johnson, P., Prusiner, S. B., Hooles, M. E., and Ghetti, B. (1992) Linkage of the Indiana kindred of GerstmannSträussler-Scheinker disease to the prion protein gene, Nature Genet. 1, 64–67.PubMedCrossRefGoogle Scholar
  25. a. Unverzagt, F. W., Farlow, M. R., Norton, J., Dlouhy, S. R., Young, K., and Ghetti, B. Neurophysiological function in patients with Gerstmann-Sträussler-Scheinker disease from the Indiana Kindred (F198S), in press.Google Scholar
  26. 25.
    Bolton, D. C., McKinley, M. P., and Prusiner, S. B. (1982) Identification of a protein that purifies with the scrapie protein, Science 218, 1309, 1310.Google Scholar
  27. 26.
    Kascsak, R. J., Rubenstein, R., Merz, P. A., Carp, R. I., Robakis, N. K., Wisniewski, H. M., and Diringer, H. (1986) Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains, J. Virol. 59, 676–683.Google Scholar
  28. 27.
    Rubenstein, R., Merz, P. A., Kascsak, R. J., Carp, R. I., Scalici, C. L., Fama, C. L., and Wisniewski, H. M. (1987) Detection of scrapie-associated fibrils (SAF) and SAF proteins from scrapie-affected sheep, J. Infect. Dis. 156, 36–42.PubMedCrossRefGoogle Scholar
  29. 28.
    Hope, J., Ritchie, L., Farquhar, C., Somerville, R., and Hunter, N. (1989) Bovine spongifonn encephalopathy: a scrapie-like disease of British cattle, Prog. Clin. Biol. Res. 317, 659–667.PubMedGoogle Scholar
  30. 29.
    Brown, P., Coker-Vann, M., Pomeroy, K., Franko, M., Asher, D. M., Gibbs, C. J., and Gajdusek, D. C. (1986) Diagnosis of Creutzfeldt-Jakob disease by western blot identification of marker protein in human brain tissue, N. Engl. J. Med. 314, 547–551.PubMedCrossRefGoogle Scholar
  31. 30.
    Bockman, J. M., Kingsbury, D. R., McKinley, M. P., Bendheim, P. E., and Prusiner, S. B. (1985) Creutzfeldt-Jakob disease prion proteins in human brains, N. Engl. J Med. 312, 73–78.PubMedCrossRefGoogle Scholar
  32. 31.
    Bessen, R. A. and Marsh, R. F. (1994) Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy, J. Virol. 68, 7859–7868.PubMedGoogle Scholar
  33. 32.
    Monari, L., Chen, S. C., Brown, P., Parchi, P., Petersen, R. B., Mikol, J., Gray, F., Cortelli, P., Montagna, P., Ghetti, B., Goldfarb, L. G., Gajdusek, D. C., Lugaresi, E., Gambetti, P., and Autilio-Gambetti, L. (1994) Fatal Familial Insomnia and Familial Creutzfeldt-Jakob disease: Different prion proteins determined by a DNA polymorphism, Proc. Natl. Acad. Sci. USA, 91, 2839–2842.PubMedCrossRefGoogle Scholar
  34. 33.
    Tagliavini, F., Prelli, F., Ghiso, J., Bugiani, O., Serban, D., Prusiner, S. B., Farlow, M. R., Ghetti, B., and Frangione, B. (1991) Amyloid protein of Gertsmann-Straussler-Scheinker disease (Indiana kindred) is an l lkd fragment of prion protein with an N-terminal glycine at codon 58, EMBO J. 10, 513–519.PubMedGoogle Scholar
  35. 34.
    Brandner, S., Isenmann, S., Raeber, A., Fischer, M., Sailer, A., Kobayashi, Y., Marino, S., Weissmann, C., and Aguzzi, A. (1996) Normal host prion protein necessary for scrapieinduced neurotoxicity, Nature 379, 339–343.PubMedCrossRefGoogle Scholar
  36. 35.
    Collinge, J., Whittington, M. A., Sidle, K. C., Smith, C. J., Palmer, M. S., Clarke, A. R., and Jefferys, J. G. R. (1994) Prion protein is necessary for normal synaptic function, Nature 370, 295–297.PubMedCrossRefGoogle Scholar
  37. 36.
    Jendroska, K., Heinzel, F. P., Torchia, M., Stowring, L., Kretzschmar, H. A., Kon, A., Stern, A., Prusiner, S. B., and DeArmond, S. J. (1991) Proteinase-resistant prion protein accumulation in Syrian hamster brain correlations with regional pathology and scrapie infectivity, Neurology 41, 1482–1490.PubMedCrossRefGoogle Scholar
  38. 37.
    Castellani, R., Parchi, P., Stahl, J., Capellari, S., Cohen, M., and Gambetti, P. (1996) Early pathological and biochemical changes in Creutzfeldt-Jakob disease: study of brain biopsies, Neurology 46, 1690–1693.PubMedCrossRefGoogle Scholar
  39. 38.
    Kitamoto, T., Shin, R. W., Doh-ura, K., Tomokane, N., Miyazono, M., Muramoto, T., and Tateishi, J. (1992) Abnormal isoform of prion proteins accumulates in the synaptic struc-tures of the central nervous system in patients with Creutzfeldt-Jakob disease, Am. J. Pathol. 140, 1285–1294.PubMedGoogle Scholar
  40. 39.
    Jeffrey, M., Goodsir, C. M., Bruce, M., McBride, P. A., Scott, J. R., and Halliday, W. G. (1994) Correlative light and electron microscopy studies of PrP localization in 87V scrapie, Brain Res. 656, 329–343.PubMedCrossRefGoogle Scholar
  41. 40.
    Clinton, J., Forsyth, C., Royston, M. C., and Roberts, G. W. (1993) Synaptic degeneration is the primary neuropathological feature in prion disease: a preliminary study, NeuroReport 4, 65–68.PubMedCrossRefGoogle Scholar
  42. 41.
    Forloni, G., Angeretti, N., Chiesa, R., Monzani, E., Salmona, M., Bugiani, O., and Tagliavini, F. (1993) Neurotoxicity of a prion protein fragment, Nature 362, 543–546.PubMedCrossRefGoogle Scholar
  43. 42.
    Brown, D. R., Herms, J., and Kretzschmar, H. A. (1994) Mouse cortical cells lacking cellular PrP survive in culture with a neurotoxic PrP fragment, NeuroReport 5, 2057–2060.PubMedCrossRefGoogle Scholar
  44. 43.
    Shyng, S. L., Huber, M. T., and Harris, D. A. (1993) A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells, J. Biol. Chem. 268, 15,922–15, 928.Google Scholar
  45. 44.
    Chen, S. G., Teplow, D. B., Parchi, P., Teller, J. K., Gambetti, P., and Autilio-Gambetti, L. (1995) Truncated forms of the human prion protein in normal brain and in prion diseases, J. Biol. Chem. 270, 19,173–19, 180.Google Scholar
  46. 45.
    Ghetti, B., Piccardo, P., Frangione, B., Bugiani, O., Giaccone, G., Young, K., Prelli, F., Farlow, M. R., Dloughy, S. R., and Tagliavini, F. (1996) Prion protein amyloidosis, Brain Pathol. 6, 127–145.PubMedCrossRefGoogle Scholar
  47. 46.
    Piccardo, P., Ghetti, B., Dickson, D. W., Vinters, H. V., Giaccone, G., Bugiani, O., Tagliavini, F., Young, K., Phil, D., Dloughy, S. R., Seiler, C., Jones, C. K., Lazzarini, A., Golbe, L. I., Zimmerman, T. R., Perlman, S. L., McLachlan, D. C., St. George-Hyslop, P. H., and Lennox, A. (1995) Gertsmann-Straussler-Scheinker disease (PRNP P102L): Amyloid deposits are best recognized by antibodies directed to epitopes in PrP region 90–165, J. Neurol. Exp. Neurol. 54, 790–801.CrossRefGoogle Scholar
  48. 47.
    Hainfellner, J. A., Brantner-Inthaler, S., Cervenakova, L., Brown, P., Kitamoto, T., Tateishi, J., Diringer, H., Liberski, P. P., Regele, H., Feucht, M., Mayr, N., Wessely, P., Summer, K., Seitelberger, F., and Budka, H. (1995) The original Gertsmann-Sträussler-Scheinker family ofAustria: Divergent clinicopathological phenotypes but constant PrP genotype, Brain Pathol. 5, 201–211.PubMedCrossRefGoogle Scholar
  49. 48.
    Tagliavini, F., Prelli, F., Verga, L., Giaccone, G., Sarma, R., Gorevic, P., Ghetti, B., Passerini, F., Ghibaudi, E., Forloni, G., Salmona, M., Bugiani, O., and Frangione, B. (1993) Synthetic peptides homologous to prion protein residues 106–147 form amyloid-like fibrils in vitro, Proc. Natl. Acad. Sci. USA 90, 9678–9682.PubMedCrossRefGoogle Scholar
  50. 49.
    Castano, E. M. and Frangione, B. (1995) Non-Alzheimer’s disease amyloidoses of the nervous system, Curr. Opinion Neurol. 8, 279–285.CrossRefGoogle Scholar
  51. 50.
    Petersen, R. B., Parchi, P., Richardson, S. L., Urig, C. B., and Gambetti, P. (1996) Effect of the DI78N mutation and the codon 129 polymorphism on the metabolism of the prion protein, J. Biol. Chem. 271,21, 12,661–12, 668.Google Scholar
  52. 51.
    Caughey, B. and Raymond, G. J. (1991) The scrapie-associated form of PrP is made from a cell surface precursor that is both protease-and phospholipase-sensitive, J. Biol. Chem. 266, 18,217–18, 223.Google Scholar
  53. 52.
    Chen, S. G., Parchi, P., Brown, P., Roos, R. P., Vnencak-Jones, C. L., and Gambetti, P. (1996) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: abnormal prion protein (PrPres) encoded by the mutant allele, J. Neuropath. Exp. Neurol. 55,5, Al24.Google Scholar
  54. 53.
    Collinge, J., Whittington, M. A., Sidle, K. C. L., Smith, C. J., Palmer, M. S., Clarke, A. R., and Jeffreys, J. G. R. (1994) Prion protein is necessary for normal synaptic function, Nature 370, 295–297.PubMedCrossRefGoogle Scholar
  55. 54.
    Tobler, I., Gaus, S. E., Deboer, T., Achermann, P., Fischer, M., Rülicke, T., Moser, M., Oesch, B., McBride, P. A., and Manson, J. C. (1996) Altered circadian activity rhythms and sleep in mice devoid of prion protein, Nature 380, 639–642.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Piero Parchi
  • Pierluigi Gambetti

There are no affiliations available

Personalised recommendations