Prion Diseases of Humans


Prion diseases are a group of rare fatal neurodegenerative diseases that occur in humans as well as in a number of animal species. Prion diseases are associated with the misfolding and aggregation of a normal host‐encoded cellular protein, the prion protein (PrPC), into a highly infectious and disease‐specific form (PrPSc). In humans, prion diseases are unique as they occur as sporadic, familial and acquired disorders. Prion diseases are heterogeneous in respect of their clinical, pathological and biochemical phenotype, but are generally characterised by spongiform vacuolation and the deposition of PrPSc in the brain. Unlike other protein misfolding neurodegenerative conditions, prion diseases are transmissible by ingestion or inoculation. The potential impact of secondary transmission of variant Creutzfeldt–Jakob disease by donated blood components has intensified the development of potential diagnostic and screening assays for use on biological fluids such as blood and urine.

Key Concepts

  • Prion diseases are transmissible neurodegenerative disorders that occur in humans and in a wide range of animal species.
  • Prion diseases are characterised neuropathologically by spongiform vacuolation throughout the cerebral grey matter, reactive proliferation of astrocytes and microglia, neuronal loss and, in some types, the deposition of amyloid plaques within the brain.
  • Prion diseases are associated with the conformational modification of a normal host protein, the prion protein (PrPC), into a highly infectious, protease‐resistant and disease‐associated form (PrPSc).
  • Human prion diseases are unique in that they can occur as idiopathic (sporadic), familial (genetic) or acquired (infectious) disorders.
  • Diagnostic protocols for the confirmation of prion disease depend on the detection of PrPSc within the central nervous system.

Keywords: prion diseases; TSE; prion protein; transmission; PRNP; CJD; PrPC; PrPSc; PrPres

Figure 1. Pathological features in human prion disease. (a) Microvacuolar degeneration in the frontal cortex in sCJD, MM1 subtype (haematoxylin and eosin stain). (b) Astrocytes immunolabelled for glial fibrillary acidic protein in the thalamus in vCJD. (c) A kuru plaque (arrow) within the granular layer of the cerebellum in sCJD, MV2 subtype (haematoxylin and eosin stain). Prion protein immunohistochemistry in frontal cortex tissue in (d) vCJD and (e) iCJD. (f) Prion protein immunohistochemistry within the spleen in vCJD.
Figure 2. PrP conversion in sporadic, familial and acquired prion diseases. In sporadic prion disease, a chance conversion of PrPC (spheres), to PrPSc (brown cubes) results in the replication of PrPSc. In familial prion disease, the mutant PrPC (white cube) may be predisposed to conversion. In acquired forms, an exogenous source of PrPSc promotes further PrPSc conversion. A failure of the cellular mechanisms for the clearance and degradation of misfolded proteins may be a factor in the aetiology of prion diseases. In all forms of the disease, a common mechanism for replication may exist, known as seeded polymerisation, in which PrPC becomes incorporated into growing aggregates of PrPSc. Disruption of these aggregates provides further seeds for conversion.
Figure 3. Relationship between human PrP primary structure and PrPres Western blot banding patterns. (a) Schematic diagram of human PrP primary structure showing the location of epitopes for the anti‐PrP monoclonal antibody 3F4 (commonly used in Western blot analysis of PrPres) and the regions corresponding to the 18–30 kDa PrPres bands and the ∼8 kDa PrPres band. Blue circles indicate the position of the glycan moieties at amino acids 181 and 197. The two horizontal lines at the top indicate the extent of PrP that is resistant to PK digestion in the type 1 and 2 subtypes, whereas the ∼8 kDa PrPres fragment associated with GSS and VPSPr is indicated by a red horizontal line. (b) Schematic diagram indicating the approximate migration positions of bands obtained when samples from sCJD , vCJD, GSS or VPSPr brain are treated with PK and analysed by immunoblotting using the 3F4 (epitope amino acids 106–112). Molecular subtypes can be distinguished according to the extent of truncation of the unglycosylated fragment (e.g. type 1 versus 2) and the relative densities of the bands associated with the di‐ and monoglycosylated fragments (e.g. type 2A versus 2B). It should be noted that GSS can be associated with ∼8 kDa PrPres and/or the type 1 PrPres molecular profile.
Figure 4. Clinical investigations in human prion diseases. (a) Diffusion weighted imaging (DWI), MRI image in sCJD showing asymmetrical high signal in the caudate heads and anterior putamina, (arrows) more prominent on the left hemisphere. (b) DWI sequences showing cortical ribboning on the left, most evident in the frontal and anterior cingulate regions (arrow); atrophy is also evident, which can be a late feature. (c) Fluid attenuation inversion recovery (FLAIR) MRI image showing the pulvinar sign in vCJD (arrows). Reproduced with permission from Letourneau‐Guillon et al. () © John Wiley and Sons. (d) A section of EEG from a patient with sCJD showing the characteristic triphasic periodic sharp wave complexes between 1 and 2 Hz.
Figure 5. Patterns of pathology in human prion diseases. (a) Immunohistochemistry for PrP showing a synaptic/granular pattern of accumulation in the cerebral cortex in sCJD MM1 subtype. (b) Perivacuolar accumulation of PrP in the frontal cortex in sCJD MM2 subtype. (c) Intensely labelled kuru plaques within the granular layer of the cerebellum in the sCJD MV2 subtype. (d) Small intensely labelled microplaques within the molecular layer of the cerebellum in a case of VPSPr. (e) The presence of multicentric PrP–amyloid plaques in the cerebellar cortex in GSS. (f) Florid plaques in vCJD with surrounding spongiform change. Haematoxylin and eosin stain. (g) Immunohistochemistry for PrP in the frontal cortex in vCJD showing florid plaques, small cluster plaques and diffuse PrP deposits. (h) Immunohistochemistry of follicular dendritic cells within germinal centres of the tonsil in vCJD.


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Further reading

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Ritchie, Diane L, Peden, Alexander H, Urwin, Patrick JM, and Ironside, James W(Apr 2015) Prion Diseases of Humans. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000426]