Prion Diseases of Humans

Abstract

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.
close

References

Alper T, Haig DA and Clarke MC (1966) The exceptionally small size of the scrapie agent. Biochemical and Biophysical Research Communications 22 (3): 278–284.

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: 175–178.

Bell JE, Gentleman SM, Ironside JW, et al. (1997) Prion protein immunocytochemistry – UK five centre consensus report. Neuropathology and Applied Neurobiology 23: 26–35.

Bishop MT, Pennington C, Heath CA, Will RG and Knight RS (2009) PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non‐synonymous polymorphism. BMC Medical Genetics 10: 146.

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.

Bolton DC, McKinley MP and Prusiner SB (1982) Identification of a protein that purifies with the scrapie prion. Science 218: 1309–1311.

Bruce M, Chree A, McConnell I, et al. (1994) Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philosophical Transactions of the Royal Society B: Biological Sciences 343: 405–411.

Budka H (2003) Neuropathology of prion diseases. British Medical Bulletin 66: 121–130.

Castilla J, Saa P, Morales R, et al. (2006) Protein misfolding cyclic amplification for diagnosis and prion propagation studies. Methods in Enzymology. 412: 3–21.

Collinge J, Sidle KC, Meads J, Ironside J and Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383: 685–690.

Collinge J, Whitfield J, McKintosh E, et al. (2006) Kuru in the 21st century – an acquired human prion disease with very long incubation periods. Lancet 367: 2068–2074.

Cuillé J and Chelle P‐L (1936) La maladie dite tremblante du mouton, est‐elle inoculable? Les Comptes Rendus de l'Académie des sciences 203: 1552–1554.

Cuillé J and Chelle P (1939) Transmission expérimental de la tremblante chez la chévre. Les Comptes Rendus de l'Académie des sciences 208: 1058–1060.

Duffy P, Wolf J and Collins G (1974) Possible person‐to‐person transmission of Creutzfeldt‐Jakob disease. New England Journal of Medicine 290: 692–693.

Edgeworth JA, Farmer M, Sicilia A, et al. (2011) Detection of prion infection in variant Creutzfeldt‐Jakob disease: a blood‐based assay. Lancet 377: 487–493.

Gajdusek DC, Gibbs CJ and Alpers M (1966) Experimental transmission of a Kuru‐like syndrome to chimpanzees. Nature 209: 794–796.

Gambetti P, Kong Q, Zou W, Parchi P and Chen SG (2003) Sporadic and familial CJD: classification and characterisation. British Medical Bulletin 66: 213–239.

Gibbs CJ Jr Gajdusek DC, Asher DM, et al. (1968) Creutzfeldt‐Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 161: 388–389.

Gill ON, Spencer Y, Richard‐Loendt A, et .al (2013) Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. British Medical Journal 347: f5675.

Glatzel M and Aguzzi A (2000) Peripheral pathogenesis of prion diseases. Microbes and Infection 2: 613–619.

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

Hadlow WJ (1959) Scrapie and kuru. Lancet 2: 289–290.

Head MW, Ritchie D, Smith N, et al. (2004) Peripheral tissue involvement in sporadic, iatrogenic, and variant Creutzfeldt‐Jakob disease: an immunohistochemical, quantitative, and biochemical study. American Journal of Pathology 164: 143–153.

Holmes BB and Diamond MI (2014) Prion‐like properties of Tau protein: the importance of extracellular Tau as a therapeutic target. Journal of Biological Chemistry 289: 19855–19861.

Ironside JW (1996) Review: Creutzfeldt‐Jakob disease. Brain Pathology 6: 379–388.

Jarrett JT and Lansbury PT Jr (1993) Seeding “one‐dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73: 1055–1058.

Klatzo I, Gajdusek DC and Zigas V (1959) Pathology of Kuru. Laboratory Investigation 8: 799–847.

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

Letourneau‐Guillon L, Wada R and Kucharczyk W (2012) Imaging of prion diseases. Journal of Magnetic Resonance Imaging 35: 998–1012.

Linden R, Martins VR, Prado MA, et al. (2008) Physiology of the prion protein. Physiology Review 88: 673–728.

McKinley MP, Bolton DC and Prusiner SB (1983) A protease‐resistant protein is a structural component of the scrapie prion. Cell 35: 57–62.

Meyer RK, McKinley MP, Bowman KA, et al. (1986) Separation and properties of cellular and scrapie prion proteins. Proceedings of the National Academy of Sciences of the United States of America 83: 2310–2314.

Moda F, Gambetti P, Notari S, et al. (2014) Prions in the urine of patients with variant Creutzfeldt‐Jakob disease. New England Journal of Medicine 371 (6): 530–539.

Nurmi MH, Bishop M, Strain L, et al. (2003) The normal population distribution of PRNP codon 129 polymorphism. Acta Neurologica 108: 374–378.

Oesch B, Westaway D, Walchli M, et al. (1985) A cellular gene encodes scrapie PrP 27–30 protein. Cell 40: 735–746.

Orru CD, Bongianni M, Tonoli G, et al. (2014) A test for Creutzfeldt‐Jakob disease using nasal brushings. New England Journal of Medicine 371: 519–529.

Pan KM, Baldwin M, Nguyen J, et al. (1993) Conversion of alpha‐helices into beta‐sheets features in the formation of the scrapie prion proteins. Proceedings of the National Academy of Sciences of the United States of America 90: 10962–10966.

Parchi P, CastellaniR CS, et al. (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt‐Jakob disease. Annals of Neurology 39: 767–778.

Parchi P, Petersen RB, Chen SG, et al. (1998) Molecular pathology of fatal familial insomnia. Brain Pathology 8: 539–548.

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: 224–233.

Peden AH, Head MW and Ironside JW (2013) Risk of transmission of Creutzfeldt‐Jakob disease by blood transfusion. In: Zou WQ and Gambetti P, (eds). Prions and Diseases, pp. 121–138. New York: Springer.

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

Prusiner SB, BoltonDC GDF, et al. (1982) Further purification and characterization of scrapie prions. Biochemistry 21: 6942–6950.

Prusiner SB and DeArmond SJ (1994) Prion diseases and neurodegeneration. Annual Review Neuroscience 17: 311–339.

Ritchie DL, Head MW and Ironside JW (2004) Advances in the detection of prion protein in peripheral tissues of variant Creutzfeldt–Jakob disease patients using paraffin‐embedded tissue blotting. Neuropathology and Applied Neurobiology 30: 360–368.

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

Safar J, Roller PP, Gajdusek DC and Gibbs CJ Jr (1993) Conformational transitions, dissociation and unfolding of scrapie amyloid (prion) protein*. Journal of Biological Chemistry 268: 20276–20284.

Telling GC, Parchi P, DeArmond SJ, et al. (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274: 2079–2082.

Westergard L, Christensen HM and Harris DA (2007) The cellular prion protein (PrP(C)): its physiological function and role in disease. Biochimica et Biophysica Acta 1772: 629–644.

Wilham JM, Orru CD, Bessen RA, et al. (2010) Rapid end‐point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathogens 6: e1001217.

Further reading

Aguzzi A and Calella AM (2009) Prions: protein aggregation and infectious disease. Physiological Review 89 (14): 1105–1152.

Budka H, Head MW, Ironside JW, et al. (2011) Sporadic Creutzfeldt‐Jakob disease. In: Dickson DW and Weller RO, (eds). Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, pp. 322–325. Oxford: Wiley‐Blackwell.

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.

Ironside JW, Ghetti B, Head MW, Piccardo P and Will RG (2008) Prion diseases. In: Love S, Louis DN and Ellison DW, (eds). Greenfield's Neuropathology, 8th edn, pp. 1197–1273. London: Hodder Arnold.

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

* Required Field

How to Cite close
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. http://www.els.net [doi: 10.1002/9780470015902.a0000426]