Prions

Abstract

Prion diseases are invariably fatal neurodegenerative disorders associated with the aberrant folding of the normal cellular prion protein. The disease affects both humans and animals and in humans occurs in sporadic, familial and acquired forms. In the absence of a conventional infectious agent, the acquired forms of the disease occur through the transmission of the misfolded form of the prion protein, or prion. This article highlights the evidence for the principle of a ‘protein‐only’ transmissible disease and addresses some of the controversies including the existence of prion strains and the species barrier. It will also consider the expanding spectrum of ‘prion‐like’ diseases.

Key Concepts

  • An overview of prion diseases that affect humans and animals.
  • Biology of the cellular prion protein.
  • Prion protein misfolding and disease.
  • Proving the ‘protein‐only’ hypothesis.
  • The molecular basis of the species barrier and prion strains.
  • An introduction to ‘prion‐like’ protein aggregation.

Keywords: prion; transmissible spongiform encephalopathy; PrPC ; PrPSc ; protein misfolding

Figure 1. Schematic representation of PrPC, showing cleavage of the signal peptide at residue 23 and addition of GPI at residue 232, octapeptide repeats (shaded boxes), two N‐linked glycosylation sites (○), di‐sulphide bond (S‐S) and codon 129. PrPC can undergo α‐cleavage at reside 111/112 to produce the C1 fragment or β‐cleavage around residue 90 to produce the C2 fragment that also represents the protease‐resistant core of PrPSc. The normally protease‐sensitive form of PrPC misfolds to form PrPSc, which can be detected following proteinase K digestion and Western immunoblot analysis. The electrophoretic mobility of PrPSc following PK digestion can also distinguish between sporadic CJD types and differences in glycoform (di‐, mono‐ and unglycosylated PrP) can be used to identify variant CJD.
Figure 2. The effect of PrPC expression on susceptibility to prion disease. Following inoculation with mouse or hamster‐adapted prions, mice succumb to clinical prion disease (x). Arrow indicates the length of the incubation period. Prnp knock‐out (0xPrnp), Prnp heterozygous (1xPrnp), Prnp wild‐type (2xPrnp), Prnp overexpressing (60xPrnp), Prnp conditional knock out (NFH‐Cre/Tg), Prnp knock down (Prnp siRNA), hamster Prnp transgenic (Tg HaPrnp) and Prnp without the GPI anchor (GPI‐/Tg) mice are shown. Spontaneous disease that could be subsequently passaged to wild‐type mice has been reported in transgenic mice expressing the E200K or D177N mutations associated with familial prion disease.
Figure 3. Proving the protein‐only hypothesis. The cell‐free conversion assay (a) demonstrated that brain‐derived PrPSc could confer protease resistance on radiolabelled PrPC. The protein misfolding cyclic amplification assay (b) demonstrated that prion‐infected brain could confer protease resistance on brain‐derived prion protein. Folding of recombinant PrP into amyloid fibrils (c) was shown to cause disease when inoculated into transgenic mice. Sonication and incubation of purified mammalian PrPC with cofactors to generate protease‐resistant PrP (d) was shown to cause disease when inoculated into wild‐type mice. Sonication and incubation of recombinant PrP with cofactors to generate protease‐resistant PrP (e) was shown to cause disease when inoculated into wild‐type mice.
close

References

Atarashi R , Satoh K , Sano K , et al. (2011) Ultrasensitive human prion detection in cerebrospinal fluid by real‐time quaking‐induced conversion. Nature Medicine 17 (2): 175–178.

Balducci C , Beeg M , Stravalaci M , et al. (2010) Synthetic amyloid‐beta oligomers impair long‐term memory independently of cellular prion protein. Proceedings of the National Academy of Sciences of the United States of America 107 (5): 2295–2300.

Beekes M and McBride PA (2007) The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies. FEBS Journal 274 (3): 588–605.

Bessen RA and Marsh RF (1992a) Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. Journal of Virology 66 (4): 2096–2101.

Bessen RA and Marsh RF (1992b) Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. Journal of General Virology 73 (Pt 2): 329–334.

Bishop MT , Will RG and Manson JC (2010) Defining sporadic Creutzfeldt‐Jakob disease strains and their transmission properties. Proceedings of the National Academy of Sciences of the United States of America 107 (26): 12005–12010.

Brachmann A , Baxa U and Wickner RB (2005) Prion generation in vitro: amyloid of Ure2p is infectious. EMBO Journal 24 (17): 3082–3092.

Brandner S , Isenmann S , Raeber A , et al. (1996) Normal host prion protein necessary for scrapie‐induced neurotoxicity. Nature 379 (6563): 339–343.

Brown P , Brandel JP , Sato T , et al. (2012) Iatrogenic Creutzfeldt‐Jakob disease, final assessment. Emerging Infectious Diseases 18 (6): 901–907.

Brown P , Gibbs CJ Jr Rodgers‐Johnson P , et al. (1994) Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Annals of Neurology 35 (5): 513–529.

Brown P , Preece M , Brandel JP , et al. (2000) Iatrogenic Creutzfeldt‐Jakob disease at the millennium. Neurology 55 (8): 1075–1081.

Bueler H , Aguzzi A , Sailer A , et al. (1993) Mice devoid of PrP are resistant to scrapie. Cell 73 (7): 1339–1347.

Castilla J , Saa P , Hetz C and Soto C (2005) In vitro generation of infectious scrapie prions. Cell 121 (2): 195–206.

Caughey B , Raymond GJ and Bessen RA (1998) Strain‐dependent differences in beta‐sheet conformations of abnormal prion protein. Journal of Biological Chemistry 273 (48): 32230–32235.

Caughey B , Raymond GJ , Ernst D and Race RE (1991) N‐terminal truncation of the scrapie‐associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease‐resistant state. Journal of Virology 65 (12): 6597–6603.

Chakrabarti O and Hegde RS (2009) Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration. Cell 137 (6): 1136–1147.

Chakrabarti O , Rane NS and Hegde RS (2011) Cytosolic aggregates perturb the degradation of nontranslocated secretory and membrane proteins. Molecular Biology of the Cell 22 (10): 1625–1637.

Chen SG , Teplow DB , Parchi P , et al. (1995) Truncated forms of the human prion protein in normal brain and in prion diseases. Journal of Biological Chemistry 270 (32): 19173–19180.

Chesebro B , Race R , Wehrly K , et al. (1985) Identification of scrapie prion protein‐specific mRNA in scrapie‐infected and uninfected brain. Nature 315 (6017): 331–333.

Chesebro B , Trifilo M , Race R , et al. (2005) Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308 (5727): 1435–1439.

Collins SJ , Sanchez‐Juan P , Masters CL , et al. (2006) Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt‐Jakob disease. Brain 129 (Pt 9): 2278–2287.

Deleault NR , Harris BT , Rees JR and Supattapone S (2007) From the Cover: Formation of native prions from minimal components in vitro. Proceedings of the National Academy of Sciences of the United States of America 104 (23): 9741–9746.

Edskes HK , Khamar HJ , Winchester CL , et al. (2014) Sporadic distribution of prion‐forming ability of Sup35p from yeasts and fungi. Genetics 198 (2): 605–616.

Falsig J , Julius C , Margalith I , et al. (2008) A versatile prion replication assay in organotypic brain slices. Nature Neuroscience 11 (1): 109–117.

Falsig J , Sonati T , Herrmann US , et al. (2012) Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures. PLoS Pathogens 8 (11): e1002985.

Fischer M , Rulicke T , Raeber A , et al. (1996) Prion protein (PrP) with amino‐proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO Journal 15 (6): 1255–1264.

Forloni G , Angeretti N , Chiesa R , et al. (1993) Neurotoxicity of a prion protein fragment. Nature 362 (6420): 543–546.

Gambetti P , Dong Z , Yuan J , et al. (2008) A novel human disease with abnormal prion protein sensitive to protease. Annals of Neurology 63 (6): 697–708.

Gimbel DA , Nygaard HB , Coffey EE , et al. (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. Journal of Neuroscience 30 (18): 6367–6374.

Goldmann W , Hunter N , Smith G , Foster J and Hope J (1994) PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. Journal of General Virology 75 (Pt 5): 989–995.

Gonzalez‐Montalban N , Lee YJ , Makarava N , Savtchenko R and Baskakov IV (2013) Changes in prion replication environment cause prion strain mutation. FASEB Journal 27 (9): 3702–3710.

Gordon WS (1946) Advances in veterinary research. Veterinary Record 58 (47): 516–525.

Govaerts C , Wille H , Prusiner SB and Cohen FE (2004) Evidence for assembly of prions with left‐handed beta‐helices into trimers. Proceedings of the National Academy of Sciences of the United States of America 101 (22): 8342–8347.

Griffith JS (1967) Self‐replication and scrapie. Nature 215 (105): 1043–1044.

Groveman BR , Dolan MA , Taubner LM , et al. (2014) Parallel in‐register intermolecular beta‐sheet architectures for prion‐seeded prion protein (PrP) amyloids. Journal of Biological Chemistry 289 (35): 24129–24142.

Hegde RS , Mastrianni JA , Scott MR , et al. (1998) A transmembrane form of the prion protein in neurodegenerative disease. Science 279 (5352): 827–834.

Hill AF , Desbruslais M , Joiner S , et al. (1997) The same prion strain causes vCJD and BSE. Nature 389 (6650): 448–450, 526.

Hill AF , Joiner S , Wadsworth JD , et al. (2003) Molecular classification of sporadic Creutzfeldt‐Jakob disease. Brain 126 (Pt 6): 1333–1346.

Hsiao KK , Groth D , Scott M , et al. (1994) Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proceedings of the National Academy of Sciences of the United States of America 91 (19): 9126–9130.

Hsiao K , Scott M , Foster D , et al. (1991) Spontaneous neurodegeneration in transgenic mice with prion protein codon 101 proline—leucine substitution. Annals of the New York Academy of Sciences 640: 166–170.

Jackson WS , Borkowski AW , Faas H , et al. (2009) Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice. Neuron 63 (4): 438–450.

Jackson WS , Borkowski AW , Watson NE , et al. (2013) Profoundly different prion diseases in knock‐in mice carrying single PrP codon substitutions associated with human diseases. Proceedings of the National Academy of Sciences of the United States of America 110 (36): 14759–14764.

Jimenez‐Huete A , Lievens PM , Vidal R , et al. (1998) Endogenous proteolytic cleavage of normal and disease‐associated isoforms of the human prion protein in neural and non‐neural tissues. American Journal of Pathology 153 (5): 1561–1572.

King CY and Diaz‐Avalos R (2004) Protein‐only transmission of three yeast prion strains. Nature 428 (6980): 319–323.

Kocisko DA , Come JH , Priola SA , et al. (1994) Cell‐free formation of protease‐resistant prion protein. Nature 370 (6489): 471–474.

Lauren J , Gimbel DA , Nygaard HB , Gilbert JW and Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid‐beta oligomers. Nature 457 (7233): 1128–1132.

Lawson VA , Vella LJ , Stewart JD , et al. (2008) Mouse‐adapted sporadic human Creutzfeldt‐Jakob disease prions propagate in cell culture. International Journal of Biochemistry & Cell Biology 40 (12): 2793–2801.

Legname G , Baskakov IV , Nguyen HO , et al. (2004) Synthetic mammalian prions. Science 305 (5684): 673–676.

Lewis V , Hill AF , Haigh CL , et al. (2009) Increased proportions of C1 truncated prion protein protect against cellular M1000 prion infection. Journal of Neuropathology and Experimental Neurology 68 (10): 1125–1135.

Llewelyn CA , Hewitt PE , Knight RS , et al. (2004) Possible transmission of variant Creutzfeldt‐Jakob disease by blood transfusion. Lancet 363 (9407): 417–421.

Luk KC , Kehm V , Carroll J , et al. (2012) Pathological alpha‐synuclein transmission initiates Parkinson‐like neurodegeneration in nontransgenic mice. Science 338 (6109): 949–953.

Ma J , Wollmann R and Lindquist S (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298 (5599): 1781–1785.

Mallucci G , Dickinson A , Linehan J , et al. (2003) Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302 (5646): 871–874.

Mallucci GR , White MD , Farmer M , et al. (2007) Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion‐infected mice. Neuron 53 (3): 325–335.

Manson JC , Jamieson E , Baybutt H , et al. (1999) A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO Journal 18 (23): 6855–6864.

Moore RC , Hope J , McBride PA , et al. (1998) Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent. Nature Genetics 18 (2): 118–125.

Nazor KE , Kuhn F , Seward T , et al. (2005) Immunodetection of disease‐associated mutant PrP, which accelerates disease in GSS transgenic mice. EMBO Journal 24 (13): 2472–2480.

O'Rourke KI , Spraker TR , Hamburg LK , et al. (2004) Polymorphisms in the prion precursor functional gene but not the pseudogene are associated with susceptibility to chronic wasting disease in white‐tailed deer. Journal of General Virology 85 (Pt 5): 1339–1346.

Palmer MS , Dryden AJ , Hughes JT and Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt‐Jakob disease. Nature 352 (6333): 340–342.

Parchi P , Giese A , Capellari S , et al. (1999) Classification of sporadic Creutzfeldt‐Jakob disease based on molecular and phenotypic analysis of 300 subjects. Annals of Neurology 46 (2): 224–233.

Parkin ET , Watt NT , Hussain I , et al. (2007) Cellular prion protein regulates beta‐secretase cleavage of the Alzheimer's amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America 104 (26): 11062–11067.

Peden AH , Head MW , Ritchie DL , Bell JE and Ironside JW (2004) Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364 (9433): 527–529.

Priola SA , Chabry J and Chan K (2001) Efficient conversion of normal prion protein (PrP) by abnormal hamster PrP is determined by homology at amino acid residue 155. Journal of Virology 75 (10): 4673–4680.

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

Saborio GP , Permanne B and Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411 (6839): 810–813.

Scott M , Foster D , Mirenda C , et al. (1989) Transgenic mice expressing hamster prion protein produce species‐specific scrapie infectivity and amyloid plaques. Cell 59 (5): 847–857.

Tanaka M , Chien P , Naber N , Cooke R and Weissman JS (2004) Conformational variations in an infectious protein determine prion strain differences. Nature 428 (6980): 323–328.

Telling GC , Scott M , Mastrianni J , et al. (1995) Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83 (1): 79–90.

Um JW , Nygaard HB , Heiss JK , et al. (2012) Alzheimer amyloid‐beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature Neuroscience 15 (9): 1227–1235.

Vella LJ , Sharples RA , Lawson VA , et al. (2007) Packaging of prions into exosomes is associated with a novel pathway of PrP processing. Journal of Pathology 211 (5): 582–590.

Vilette D , Andreoletti O , Archer F , et al. (2001) Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proceedings of the National Academy of Sciences of the United States of America 98 (7): 4055–4059.

Wang F , Wang X , Yuan CG and Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327 (5969): 1132–1135.

Further Reading

Altmeppen HC , Puig B , Dohler F , et al. (2012) Proteolytic processing of the prion protein in health and disease. American Journal of Neurodegenerative Disease 1 (1): 15–31.

Kraus A , Groveman BR and Caughey B (2013) Prions and the potential transmissibility of protein misfolding diseases. Annual Review of Microbiology 67: 543–564.

Requena JR and Wille H (2014) The structure of the infectious prion protein: experimental data and molecular models. Prion 8 (1): 60–66.

Supattapone S (2014) Synthesis of high titer infectious prions with cofactor molecules. Journal of Biological Chemistry 289 (29): 19850–19854.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lawson, Victoria A(Apr 2015) Prions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000069.pub2]