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.


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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.

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Lawson, Victoria A(Apr 2015) Prions. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000069.pub2]