Key Points
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Since the early 1950s researchers have been studying slow and invariably fatal diseases such as scrapie (sheep), Creutzfeldt–Jakob disease and kuru (humans), bovine spongiform encephalopathy (cattle and sheep) and chronic wasting disease (deer) that are now known to be caused by transmissible agents dubbed 'prions'. After decades of investigation the precise structure of the prion is still debated.
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The 'protein-only' hypothesis posits that prions are congruent with PrPSc, a misfolded form of the naturally occurring 'cellular prion protein' (PrPC). PrPC is encoded by the Prnp locus and is normally attached to the cell surface by a glycosylphosphatidyl inositol (GPI) anchor. Replication of the prion is attributed to PrPSc-catalysed conversion of PrPC to PrPSc. The 'virus' and 'virino' hypotheses propose that the infectious agent contains an informational nucleic acid; however, despite the best efforts of many laboratories, no such molecule has been identified so far.
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Infectivity purified from infected brain material contains aggregates of PrPSc as the major protein component, bundled together with other substances including glycosaminoglycans and polysaccharides. Solubilization of the aggregates by denaturants causes loss of infectivity, which so far is irreversible.
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The replication of prions is discussed, together with experimental evidence obtained from whole organisms, cell lines and cell-free in vitro systems. Research into so-called 'yeast prions', self-propagating conformational isoforms of certain yeast proteins, has added experimental support to the protein-only hypothesis.
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Differences in strains and factors that affect prion transmission are considered in light of the protein-only prion hypothesis. Expression of cellular PrP is essential for susceptibility to prion disease and for prion replication, but other genes also have a modulating role. The spread of prions within organisms also requires expression of the cellular form PrPC, both within and outside the central nervous system. Certain cells of the immune system serve as amplification sites in prion spread.
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The origin and evolution of prions are considered. Misfolded PrP may have evolved to serve a useful purpose and at the same time acquired a pathogenic potential that, in early evolutionary times, when the human life span was short, did not confer a selective disadvantage. Alternatively, prions could be derived from ancient exogenous pathogens that are now fully integrated into host chromosomes. More trivially, prions are misfolded proteins that by coincidence have the ability to invade a host through the digestive tract, make their way into the lymphoreticular system where they are amplified and transfer themselves into the central nervous system, which they then destroy.
Abstract
There is little doubt that the main component of the transmissible agent of spongiform encephalopathies — the prion — is a conformational variant of the ubiquitous host protein PrPC, and that the differing properties of various prion strains are associated with different abnormal conformations of this protein. The precise structure of the prion is not yet known, nor are the mechanisms of infection, conformational conversion and pathogenesis understood.
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References
Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982). A historically important paper providing a major breakthrough in the understanding of spongiform encephalopathies.
Oesch, B. et al. A cellular gene encodes scrapie PrP 27-30 protein. Cell 40, 735–746 (1985). A historically important paper showing that the gene encoding what is believed to be the infectious molecule is encoded by the host.
Chesebro, B. et al. Identification of scrapie prion protein-specific messenger RNA in scrapie-infected and uninfected brain. Nature 315, 331–333 (1985).
Basler, K. et al. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell 46, 417–428 (1986).
Stahl, N. et al. Structural studies of the scrapie prion protein using mass spectrometry and amino acid sequencing. Biochemistry 32, 1991–2002 (1993).
Prusiner, S. B. Prions causing degenerative neurological diseases. Annu. Rev. Med. 38, 381–398 (1987).
Hsiao, K. et al. Linkage of a prion protein missense variant to Gerstmann–Sträussler syndrome. Nature 338, 342–345 (1989). Established the first genetic link between a familial prion disease and the PrP gene.
Prusiner, S. B. et al. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63, 673–686 (1990). First demonstration that susceptibility to prion disease is modulated by the sequence of the host PrP.
Büeler, H. et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582 (1992).
Büeler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993). Proof that expression of PrP is essential for prion propagation and pathogenesis.
Wickner, R. B. et al. Yeast prions act as genes composed of self-propagating protein amyloids. Adv. Protein Chem. 57, 313–334 (2001). A review of the phenomenon of yeast prions by the person who discovered them.
Riesner, D. et al. Prions and nucleic acids: search for 'residual' nucleic acids and screening for mutations in the PrP gene. Dev. Biol. Stand. 80, 173–181 (1993).
Chesebro, B. Prion protein and the transmissible spongiform encephalopathy diseases. Neuron 24, 503–506 (1999).
Manuelidis, L. Transmissible encephalopathies: speculations and realities. Viral Immunol. 16, 123–139 (2003). An overly critical assessment of the 'protein-only' hypothesis, but worth looking at.
Kimberlin, R. H. Scrapie agent: prions or virinos? Nature 297, 107–108 (1982).
Griffith, J. S. Self-replication and scrapie. Nature 215, 1043–1044 (1967). First proposal of the 'protein-only' hypothesis.
Prusiner, S. B. Molecular biology of prion diseases. Science 252, 1515–1522 (1991).
Weissmann, C. A 'unified theory' of prion propagation. Nature 352, 679–683 (1991).
Meyer, R. K. et al. Separation and properties of cellular and scrapie prion proteins. Proc. Natl Acad. Sci. USA 83, 2310–2314 (1986).
Safar, J. et al. Eight prion strains have PrPSc molecules with different conformations. Nature Med. 4, 1157–1165 (1998). Provides evidence that different prion strains are associated with different PrP conformations.
Peretz, D. et al. Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci. 10, 854–863 (2001).
Neary, K., Caughey, B., Ernst, D., Race, R. E. & Chesebro, B. Protease sensitivity and nuclease resistance of the scrapie agent propagated in vitro in neuroblastoma cells. J. Virol. 65, 1031–1034 (1991).
McKinley, M. P., Bolton, D. C. & Prusiner, S. B. A protease-resistant protein is a structural component of the scrapie prion. Cell 35, 57–62 (1983).
Kuczius, T. & Groschup, M. H. Differences in proteinase K resistance and neuronal deposition of abnormal prion proteins characterize bovine spongiform encephalopathy (BSE) and scrapie strains. Mol. Med. 5, 406–418 (1999).
Harris, D. A. et al. A transgenic model of a familial prion disease. Arch. Virol. Suppl. 103–112 (2000).
Post, K. et al. Rapid acquisition of β-sheet structure in the prion protein prior to multimer formation. Biol. Chem. 379, 1307–1317 (1998).
Appel, T. R., Dumpitak, C., Matthiesen, U. & Riesner, D. Prion rods contain an inert polysaccharide scaffold. Biol. Chem. 380, 1295–1306 (1999).
Bolton, D. C., Rudelli, R. D., Currie, J. R. & Bendheim, P. E. Copurification of Sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease. J. Gen. Virol. 72, 2905–2913 (1991).
Weissmann, C. Spongiform encephalopathies. The prion's progress. Nature 349, 569–571 (1991).
Manson, J. C. et al. A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO J. 18, 6855–6864 (1999). An interesting example of how a single amino acid change in PrP can affect pathogenesis in prion disease.
Lasmezas, C. I. et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275, 402–405 (1997).
Collinge, J. et al. Transmission of fatal familial insomnia to laboratory animals. Lancet 346, 569–570 (1995).
Manuelidis, L., Sklaviadis, T. & Manuelidis, E. E. Evidence suggesting that PrP is not the infectious agent in Creutzfeldt–Jakob disease. EMBO J. 6, 341–347 (1987).
Tzaban, S. et al. Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes. Biochemistry 41, 12868–12875 (2002).
Tremblay, P. et al. Mutant PrPSc conformers induced by a synthetic peptide and several prion strains. J. Virol. 78, 2088–2099 (2004).
Prusiner, S. B. & Scott, M. R. Genetics of prions. Annu. Rev. Genet. 31, 139–175 (1997).
Liemann, S. & Glockshuber, R. Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. Biochemistry 38, 3258–3267 (1999).
Jarrett, J. T. & Lansbury, P. J. Seeding 'one-dimensional crystallization' of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).
Orgel, L. E. Prion replication and secondary nucleation. Chem. Biol. 3, 413–414 (1996).
Vanik, D. L., Surewicz, K. A. & Surewicz, W. K. Molecular basis of barriers for interspecies transmissibility of mammalian prions. Mol. Cell 14, 139–145 (2004).
Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268, 880–884 (1995).
Wickner, R. B. et al. Prions of yeast as heritable amyloidoses. J. Struct. Biol. 130, 310–322 (2000).
Enari, M., Flechsig, E. & Weissmann, C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc. Natl Acad. Sci. USA 98, 9295–9299 (2001).
Montrasio, F. et al. B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice. Proc. Natl Acad. Sci. USA 98, 4034–4037 (2001).
Telling, G. C. et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83, 79–90 (1995).
Peretz, D. et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412, 739–743 (2001).
Priola, S. A. & Chesebro, B. A single hamster PrP amino acid blocks conversion to protease-resistant PrP in scrapie-infected mouse neuroblastoma cells. J. Virol. 69, 7754–7758 (1995).
Hunter, N. in Prion Diseases (eds Baker, H. F. & Ridley, R. M.) 211–221 (Humana Press, New Jersey, 1996).
Perrier, V. et al. Dominant-negative inhibition of prion replication in transgenic mice. Proc. Natl Acad. Sci. USA 23, 23 (2002).
Windl, O. et al. Genetic basis of Creutzfeldt–Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum. Genet. 98, 259–264 (1996).
Collinge, J. & Rossor, M. A new variant of prion disease. Lancet 347, 916–917 (1996).
Peden, A. H., Head, M. W., Ritchie, D. L., Bell, J. E. & Ironside, J. W. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364, 527–529 (2004).
Race, R. E., Fadness, L. H. & Chesebro, B. Characterization of scrapie infection in mouse neuroblastoma cells. J. Gen. Virol. 68, 1391–1399 (1987).
Rubenstein, R., Carp, R. I. & Callahan, S. M. In vitro replication of scrapie agent in a neuronal model: infection of PC12 cells. J. Gen. Virol. 65, 2191–2198 (1984).
Schatzl, H. M. et al. A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis. J. Virol. 71, 8821–8831 (1997).
Vorberg, I., Raines, A., Story, B. & Priola, S. A. Susceptibility of common fibroblast cell lines to transmissible spongiform encephalopathy agents. J. Infect. Dis. 189, 431–439 (2004).
Vilette, D. et al. Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc. Natl Acad. Sci. USA 98, 4055–4059 (2001).
Bosque, P. J. & Prusiner, S. B. Cultured cell sublines highly susceptible to prion infection. J. Virol. 74, 4377–4386 (2000).
Kloehn, P.-C., Stoltze, l., Flechsig, E., Enari, M. & Weissmann, C. A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc. Natl Acad. Sci. USA 100, 11666–11671 (2003).
Nishida, N. et al. Successful transmission of three mouse-adapted scrapie strains to murine neuroblastoma cell lines overexpressing wild-type mouse prion protein. J. Virol. 74, 320–325 (2000).
Fischer, M. et al. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 15, 1255–1264 (1996).
Kaneko, K. et al. Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc. Natl Acad. Sci. USA 94, 10069–10074 (1997).
Kuczius, T., Haist, I. & Groschup, M. H. Molecular analysis of bovine spongiform encephalopathy and scrapie strain variation. J. Infect. Dis. 178, 693–699 (1998).
Kocisko, D. A. et al. Cell-free formation of protease-resistant prion protein. Nature 370, 471–474 (1994). First demonstration that PrPC can be converted to PrPSc in a cell-free system.
Saborio, G. P., Permanne, B. & Soto, C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411, 810–813 (2001).
Deleault, N. R., Lucassen, R. W. & Supattapone, S. RNA molecules stimulate prion protein conversion. Nature 425, 717–720 (2003).
Legname, G. et al. Synthetic mammalian prions. Science 305, 673–376 (2004).
Bruce, M. E., Fraser, H., McBride, P. A., Scott, J. R. & Dickinson, A. G. in Prion Diseases of Humans and Animals (eds Prusiner, S. B., Collinge, J., Powell, J. & Anderton, B.) 497–508 (Ellis Horwood, New York, London, 1992).
Bessen, R. A. & Marsh, R. F. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J. Virol. 66, 2096–2101 (1992). First demonstration that different prion strains are associated with different forms of PrPSc.
Telling, G. C. et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274, 2079–2082 (1996).
Collinge, J., Sidle, K. C., Meads, J., Ironside, J. & Hill, A. F. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 383, 685–690 (1996). Provides biochemical evidence that the agents causing BSE and vCJD are related.
Safar, J. G. et al. Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nature Biotechnol. 20, 1147–1150 (2002).
Bellon, A. et al. Improved conformation-dependent immunoassay: suitability for human prion detection with enhanced sensitivity. J. Gen. Virol. 84, 1921–1925 (2003).
Caughey, B. et al. Methods for studying prion protein (PrP) metabolism and the formation of protease-resistant PrP in cell culture and cell-free systems. An update. Mol. Biotechnol. 13, 45–55 (1999).
Tanaka, M., Chien, P., Naber, N., Cooke, R. & Weissman, J. S. Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323–8. (2004). Elegant demonstration that two different fibrillar conformations of a yeast protein generated in vitro are propagated unchanged in yeast and underlie two different phenotypic strains. See also Ref. 76.
King, C. Y. & Diaz-Avalos, R. Protein-only transmission of three yeast prion strains. Nature 428, 319–323 (2004).
Kimberlin, R. H., Cole, S. & Walker, C. A. Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J. Gen. Virol. 68, 1875–1881 (1987).
DeArmond, S. J. et al. Selective neuronal targeting in prion disease. Neuron 19, 1337–1348 (1997).
Miller, M. W., Williams, E. S., Hobbs, N. T. & Wolfe, L. L. Environmental sources of prion transmission in mule deer. Emerg. Infect. Dis. 10, 1003–1006 (2004).
Pattison, I. H. in NINDB Monograph No. 2, Slow, Latent and Temperate Virus Infections (eds Gajdusek, D. C., Gibbs, C. J. & Alpers, M.) 249–257 (1965).
Hill, A. F. et al. Species-barrier-independent prion replication in apparently resistant species. Proc. Natl Acad. Sci. USA 97, 10248–10253 (2000).
Race, R., Raines, A., Raymond, G. J., Caughey, B. & Chesebro, B. Long-term subclinical carrier state precedes scrapie replication and adaptation in a resistant species: analogies to bovine spongiform encephalopathy and variant Creutzfeldt–Jakob disease in humans. J. Virol. 75, 10106–10112 (2001).
Asante, E. A. et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 21, 6358–6366 (2002).
Scott, M. R. et al. Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. Proc. Natl Acad. Sci. USA 94, 14279–14284 (1997).
Lloyd, S. E. et al. Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc. Natl Acad. Sci. USA 98, 6279–6283 (2001).
Stephenson, D. A. et al. Quantitative trait loci affecting prion incubation time in mice. Genomics 69, 47–53 (2000).
Moreno, C. R., Lantier, F., Lantier, I., Sarradin, P. & Elsen, J. M. Detection of new quantitative trait loci for susceptibility to transmissible spongiform encephalopathies in mice. Genetics 165, 2085–2091 (2003).
Manolakou, K. et al. Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice. Proc. Natl Acad. Sci. USA 98, 7402–7407 (2001).
Wickner, R. B. [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264, 566–569 (1994). The seminal paper linking extra-chromosomal inheritance in yeast with the self-propagating conformational variant of a protein.
Wickner, R. B., Edskes, H. K., Roberts, B. T., Pierce, M. & Baxa, U. Prions of yeast as epigenetic phenomena: high protein 'copy number' inducing protein 'silencing'. Adv. Genet. 46, 485–525 (2002).
Glover, J. R. et al. Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae. Cell 89, 811–819 (1997). Support for the seeding hypothesis.
Blättler, T. et al. PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389, 69–73 (1997). Shows that PrP is required not only for susceptibility to prion infection but also for prion transport through the organism.
Brandner, S. et al. Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. Proc. Natl Acad. Sci. USA 93, 13148–13151 (1996).
Huang, F. P., Farquhar, C. F., Mabbott, N. A., Bruce, M. E. & MacPherson, G. G. Migrating intestinal dendritic cells transport PrPSc from the gut. J. Gen. Virol. 83, 267–271 (2002).
Klein, M. A. et al. PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Med. 4, 1429–1433 (1998).
Kitamoto, T., Muramoto, T., Mohri, S., Dohura, K. & Tateishi, J. Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt–Jakob disease. J. Virol. 65, 6292–6295 (1991).
Mackay, F. & Browning, J. L. Turning off follicular dendritic cells. Nature 395, 26–27 (1998).
Montrasio, F. et al. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288, 1257–1259 (2000).
Mabbott, N. A., Mackay, F., Minns, F. & Bruce, M. E. Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nature Med. 6, 719–720 (2000).
Mabbott, N. A., Young, J., McConnell, I. & Bruce, M. E. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J. Virol. 77, 6845–6854 (2003).
Glatzel, M., Heppner, F. L., Albers, K. M. & Aguzzi, A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31, 25–34 (2001).
Race, R., Oldstone, M. & Chesebro, B. Entry versus blockade of brain infection following oral or intraperitoneal scrapie administration: role of prion protein expression in peripheral nerves and spleen. J. Virol. 74, 828–833 (2000).
Mallucci, G. R. et al. Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 21, 202–210 (2002).
Büeler, H. et al. High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol. Med. 1, 19–30 (1994).
Brandner, S. et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).
Mallucci, G. et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003).
Ma, J., Wollmann, R. & Lindquist, S. Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science, 1781–1785 (2002).
Ma, J. & Lindquist, S. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298, 1785–1788 (2002).
Drisaldi, B. et al. 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, 21732–21743 (2003).
Heller, U., Winklhofer, K. F., Heske, J., Reintjes, A. & Tatzelt, J. Post-translational import of the prion protein into the endoplasmic reticulum interferes with cell viability: a critical role for the putative transmembrane domain. J. Biol. Chem. 278, 36139–36147 (2003).
Roucou, X., Guo, Q., Zhang, Y., Goodyer, C. G. & LeBlanc, A. C. Cytosolic prion protein is not toxic and protects against Bax-mediated cell death in human primary neurons. J. Biol. Chem. 278, 40877–40881 (2003).
Hegde, R. S. et al. Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826 (1999).
Hegde, R. S. et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).
Carrell, R. W. & Lomas, D. A. Conformational disease. Lancet 350, 134–138 (1997).
Lansbury, P. T. Jr. Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. Proc. Natl Acad. Sci. USA 96, 3342–3324 (1999).
Flechsig, E., Manson, J. C., Barron, R., Aguzzi, A. & Weissmann, C. in Prion Biology and Diseases (ed. Prusiner, S. B.) 373–434 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2004).
Tateishi, J., Kitamoto, T., Hoque, M. Z. & Furukawa, H. Experimental transmission of Creutzfeldt–Jakob disease and related diseases to rodents. Neurology 46, 532–537 (1996).
Chiesa, R. et al. Molecular distinction between pathogenic and infectious properties of the prion protein. J. Virol. 77, 7611–7622 (2003). Discusses the difference between a PrP proteinopathy and prion disease.
Goldfarb, L. G. et al. Transmissible familial Creutzfeldt–Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the Prnp gene. Proc. Natl Acad. Sci. USA 88, 10926–10930 (1991).
Tateishi, J. & Kitamoto, T. Inherited prion diseases and transmission to rodents. Brain Pathol. 5, 53–59 (1995).
True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).
Chiti, F. et al. Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc. Natl Acad. Sci. USA 96, 3590–3594 (1999).
Weissmann, C. Molecular biology of prion diseases. Trends Cell Biol. 4, 10–14 (1994).
Weissmann, C., Enari, M., Klohn, P. C., Rossi, D. & Flechsig, E. Transmission of prions. Proc. Natl Acad. Sci. USA 14, 14 (2002).
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Glossary
- STRAINS
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Types of prions differing in regard to the clinical course of the disease and the neuropathology they elicit, their transmissibility and the physico-chemical properties of the PrP isoforms that they are associated with.
- PRION
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Protein-containing infectious agent causing transmissible spongiform encephalopathy (TSE), unusually resistant to agents known to inactivate nucleic acids. As used in this article the term does not imply any specific components or structure.
- VIRINO
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An infectious particle that is conjectured to consist of a TSE-specific nucleic acid enveloped by PrPSc.
- UNIFIED THEORY
-
This theory proposes that a PrP isoform, PrP*, is indeed the essential infectious component, but that its properties can be modified by a physically associated small RNA, the co-prion, such as a siRNA. The co-prion would have to be amplified in the host cell and remain bound to the newly formed PrP* to explain the stability of strains, and different siRNAs would be responsible for the phenotypic differences between prion strains.
- SYMPATHECTOMY
-
A chemical or surgical procedure that destroys innervation by the sympathetic nervous system.
- AMYLOID
-
Fibrillary, mostly β-sheet-rich deposits of protein. PrP in amyloid form is found in some but not all forms of prion disease in humans and animals.
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Weissmann, C. The state of the prion. Nat Rev Microbiol 2, 861–871 (2004). https://doi.org/10.1038/nrmicro1025
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DOI: https://doi.org/10.1038/nrmicro1025
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