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 and propagation of the misfolded form of the prion protein, or prion. This article will review the key clinical and pathological features of prion diseases affecting animals and humans and the characteristics of the normal and disease‐associated forms of the prion protein. It will further demonstrate how scientific research has contributed to our understanding of how a misfolded protein can transmit disease between individuals of the same and different species.

Key Concepts

  • Prion protein misfolding and disease.
  • An overview of prion diseases that affect humans and animals.
  • Biology of the cellular prion protein.
  • Proving that a protein can transmit disease.
  • What is the species barrier and prion strains.
  • An introduction to ‘prion‐like’ protein aggregation.

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

Figure 1. The hallmarks of prion disease. When compared with the unaffected brain tissue (a–c), the brain of prion‐infected mice (a′–c′) demonstrates the hallmarks of prion disease. Spongiform change is observed as holes within the tissue of the brain when stained with histological stain haematoxylin and eosin (a′). Reactive gliosis is observed as more numerous and larger cells that can be detected using a technique called immunohistochemistry (IHC) with an antibody that detects the glial fibrillary acidic protein (GFAP) expressed by glial cells (b′). Aggregates of protease‐resistant PrPSc are detected in the prion‐affected brain using IHC with an antibody that detects the prion protein. Arrows indicate these core pathologies in the prion‐affected animal brain.
Figure 2. Protein synthesis, folding and misfolding. The primary sequence of a protein is composed of amino acids whose order is determined by the genetic code enciphered within its gene. The DNA sequence of the gene is transcribed into RNA and translated into the amino acid sequence that forms the primary structure of the protein. The secondary structure of the translated protein reflects its shape that could be composed of α‐helices, β‐sheets or random coils or a combination. A cartoon of the coiled structure of an α‐helices and protein strands of a β‐sheet is shown (a). The DNA sequence of the human PrP gene ( ) is transcribed into RNA and translated into the primary amino acid sequence of PrP. The RNA and protein sequence of PrP is shown below a line representing the DNA sequence of (b). Each amino acid is encoded by a codon, the first amino acid of the prion protein, methionine (M), is encoded by the codon aug. The residue at RNA codon 129 of human PrP can encode methionine (M; aug) or valine (V; gug) and is described as a polymorphism that affects susceptibility to prion disease. When proteins misfold and have a high β‐sheet content, they can become sticky and aggregate. The aggregated proteins form structures with increasing levels of complexity. Oligomers composed of two, three or four proteins called dimers, trimers and tetramers, respectively, extend into longer metastable protofibrils which eventually mature into fibrils (c).
Figure 3. Prion diseases affect humans and animals. In humans, (a) the disease can occur for unknown reasons (sporadic), because of a mutation in the gene that encodes the prion protein (familial), acquired through surgical procedures performed on the neural tissue of any individual affected with a prion disease or the consumption of prion‐affected tissue (from cattle affected by BSE or transumption). In animals, (b) the prion diseases affecting sheep (scrapie) and deer and elk (CWD) are naturally transmissible and appear to spread from animal to animal through the environment ( ). BSE affects cattle and most likely arose from the consumption of scrapie and later BSE‐affected meat and bone meal
Figure 4. The prion protein. The features of the normal cellular form of the prion protein (PrPC) and the disease‐associated form (PrPSc) (a). 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 (residues 181 and 197; lollipops), disulfide bond (S–S) and position of the polymorphism at codon 129. PrPC can undergo α‐cleavage at reside 111/112 to produce the C1 and corresponding N1 fragment or β‐cleavage around residue 90 to produce the C2 and corresponding N2 fragment (b). The posttranslational modifications described above (glycosylation and cleavage) can be detected by the molecular weight of the protein when it is subjected to denaturation in sodium dodecyl sulfate (SDS) and polyacrylamide gel electrophoresis (SDS‐PAGE) (c). SDS‐PAGE uses an electrical current to separate the protein on the basis of size. The protein is subsequently visualised by Western immunoblotting that uses antibodies directed against the prion protein to specifically visualise the protein. The prion protein is separated as three bands, which reflect the protein without additional glycosylation (un) and the addition of glycosylation at one (mono) or two (di) N‐linked glycosylation sites. The protease sensitive form of PrPC found in uninfected tissue is completely digested by proteinase K (PK) treatment. In infected tissue, PrP misfolds to form PrPSc, which can be detected following PK digestion and Western Immunoblot analysis. Following PK treatment, the electrophoretic mobility of PrPSc present in a prion‐affected brain runs faster (closer to the bottom of the gel) because it has become smaller due to the digestion of the amino acids to around residue 90. In sporadic Creutzfeldt–Jakob disease, different prion strains have been identified by differences in their electrophoretic mobility following PK treatment. Variant Creutzfeldt–Jakob disease can be distinguished from sporadic forms of Creutzfeldt–Jakob disease as the PrPSc in cases of variant Creutzfeldt–Jakob disease has more protein that is glycosylated at both N‐linked glycosylation sites as shown by the bigger di‐glycosylated following SDS‐PAGE. See also: Gel Electrophoresis: One‐Dimensional; Western Blotting: Immunoblotting
Figure 5. Methods for studying prion disease. Prion diseases can be studied using animal models (a), using cell lines (b), in cell‐free assays (c) or using recombinant protein (d). Following inoculation with prions, wild‐type mice carrying two copies of the mouse prion protein gene (Prnp) develop prion disease. Prnp knock‐out mice do not carry any copies of the Prnp and therefore do not express the prion protein and do not develop disease when inoculated with prions. Prnp transgenic mice carry 60 copies of the Prnp and rapidly develop disease when inoculated with prions (a). Following exposure to prions, susceptible cell lines will propagate prions that can be detected as protease‐resistant protein in a cell blot assay. In the cell blot assay, infected cells are grown on a glass disc and infected cells containing PrPSc are detected as protease‐resistant PrP spots. Inoculation of the same cells with an unaffected brain homogenate does not propagate prions (b). In cell‐free assays of prion propagation, (c) PrPC derived from unaffected tissue, cell lines or recombinant protein is mixed with infected brain tissue (or cofactors that have been shown to cause the prion protein to misfold). Prion propagation is detected as an increase of protease‐resistant protein by western immunoblot (+). Recombinant PrP can be folded into the predominantly α‐helical form or folded into a shape that is rich in β‐sheet structure that may subsequently aggregate to form oligomers and more complex structures such as protofibrils and fibrils (d).


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Further Reading

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

Poggiolini I, Saverioni S and Parchi P (2013) Prion protein misfolding, strains, and neurotoxicity: an update from studies on mammalian prions. International Journal of Cell Biology 2013: 1–24, Article ID 910314.

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(Jan 2016) Prions. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026230]