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Prion Protein Mutation Database

Background

Prions were defined by Stanley Prusiner in 1982 as “proteinaceous infectious particles”1. Prion diseases are transmissible, invariably fatal, neurodegenerative disorders that may be inherited, acquired or occur spontaneously as sporadic Creutzfeldt-Jakob disease2. They also affect mammalian species, notably scrapie of sheep, chronic wasting disease of deer and elk3 and bovine spongiform encephalopathy4. Prion diseases arise consequent to misfolding and aggregation of the normal neuronal membrane constituent, prion protein (PrPC), resulting in its conversion to the pathogenic self-propagating conformer, PrPSc – an important event in the initiation and progression of the disease5-7. Thus, PrP exists in two major conformational isoforms: the non-pathogenic, predominantly α-helical, protease-sensitive cellular isoform (PrPC) and the pathogenic, partially protease-resistant scrapie-inducing isoform (PrPSc) that is enriched in β-pleated sheet structure8 – see Figure 1. PrPSc is responsible for prion propagation and constitutes the transmissible agent, able to recruit and convert natively folded PrPC. The current model of prion propagation proposes that PrPSc, either inoculated, or generated as a stochastic event from mutant PrPC (or more rarely from wild-type PrPC), interacts with PrPc and promotes its conformational conversion to PrPSc. This is thought to occur by means of seeded protein polymerisation, a process involving the binding and templated misfolding of normal cellular prion protein, such that PrPSc acts as a template to transfer its conformation onto PrPC, thereby generating new PrPSc 5,7,9. It then follows, that PrP knockout mice do not develop prion disease when challenged with scrapie10-12PrPSc accumulates in the central nervous system in heterogeneous forms; as amyloid plaques, diffuse deposits and soluble species resulting in progressive neuronal degeneration and neuronal vacuolation5,7,13-14.

Figure 1: Comparison of α-helix-predominant PrPC and β-sheet-rich PrPSc. Monomeric human PrPC features a largely disordered N-terminus (residues 23-124) and a folded C-terminal globular domain containing three α-helices, two short β-sheets and a single disulphide bond between Cys179 in α2 and Cys214 in α315. PrPSc however, is β-sheet-rich and displays the properties of infectivity, insolubility and partial protease-resistance. The structure of PrPSc is for illustration, and is that of Wang et al16, however, it is of note that this is a recombinantly produced structure whose infectivity and pathogenicity are yet to be determined. Download figure here. 

Human prion diseases affect approximately 1-1.5 persons per million worldwide annually17. Five subtypes comprise the known prion diseases: Kuru (a disease of the Fore people of Papua New Guinea related to the practice of ritualistic cannibalism of dead relatives as a symbol of respect and mourning18), sporadic Creutzfeldt-Jakob disease (CJD), familial CJD, iatrogenic CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), Fatal familial insomnia (FFI) and new variant CJD. As a group of disorders, they are unique among neurodegenerative diseases as they not only occur sporadically and are inherited genetically but can also be transmitted horizontally9. According to their aetiology, prion diseases are divided into three groups: (1) diseases acquired through infection by external prions, such is the case of Kuru, caused by consumption of an individual with sporadic CJD19-20, iatrogenic CJD transmitted by medical interventions and variant CJD caused by bovine prions21 (2-5% of CJD cases); (2) disease caused by a genetic mutations in the prion (PRNP) gene, as in the overlapping neurologic syndromes of familial CJD, GSS and FFI (approximately 10-15% of all prion diseases); and (3) sporadic CJD, that constitutes 85-90% of CJD cases and affects 1-1.5 million people per million annually2,14,17,20 (Figure 2)

The transmissible nature of these diseases was first demonstrated experimentally in 1939 by Cuillé and Chelle through intra-ocular administration of scrapie-infected spinal cord to a goat22. Nearly thirty-years later, Kuru, was transmitted to chimpanzees through intra-cerebral inoculation by Gajdusek et al in 196623, and in 1968, Gibbs et al followed suit with intra-cerebral transmission of CJD24. The aetiologic agent of these diseases is now known to be PrPSc 25-27. The classic neuropathology of prion diseases, characterised by accumulation of PrPSc in the central nervous system, comprises spongiform degeneration of the cerebral cortex and subcortical nuclei, astrocytic gliosis, vacuolation and neuronal loss. The disease itself can undergo extraordinarily long incubation periods, however, once clinical onset ensues, the course is often dramatic and relentlessly progressive. The clinically presentation is that of a neurologic or neuropsychiatric condition associated with rapid multi-focal central nervous system degeneration, usually dominated by dementia and cerebellar ataxia7,28.

Figure 2: Creutzfeldt-Jakob disease in the UK: 1990 to 2020. Reported cases of CJD in the United Kingdom. Data are from the National Creutzfeldt-Jakob Disease Surveillance Unit (http://www.cjd.ed.ac.uk) and is correct as of 2nd November 2020. Note, the data for genetic CJD includes all genetic prion diseases including GSS. 


References:

  1. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216(4542): 136-144. (PMID: 6801762)
  2. Collinge J. Prion diseases of humans and animals: their causes and molecular basis. Annual Review of Neuroscience 2001; 24: 519-550. (PMID: 11283320)
  3. Williams ES and Young S. Chronic wasting disease of captive mule deer: A spongiform encephalopathy. Journal of Wildlife Diseases 1980; 16(1): 89-98. (PMID: 7373730)
  4. Wells GA, Scott AC, Johnson CT et al. A novel progressive spongiform encephalopathy in cattle. The Veterinary Record 1987; 121(18): 419-420. (PMID: 3424605) 
  5. Collinge J, Whittington MA, Sidle KCL et al. Prion protein is necessary for normal synaptic function. Nature 1994; 370(6487): 295-297. (PMID: 8035877) 
  6. Rossetti G, Giachin G, Legname G, Carloni P. Structural facets of disease-linked human prion protein mutants: A molecular dynamic study. Proteins 2010; 78(16): 3270-3280. (PMID: 20806222)
  7. Mead S, Gandhi S, Beck J et al. A Novel Prion Disease Associated with Diarrhoea and Autonomic Neuropathy. New England Journal of Medicine 2013; 369(20): 1904-1914. (PMID: 24224623)
  8. Safar J, Roller PP, Gajdusek DC, Gibbs CJ. Conformational transitions, dissociations and unfolding of scrapie amyloid (prion) protein. Journal of Biological Chemistry 1993; 268(27): 20276-20284. (PMID: 8104185)
  9. Brown K and Mastrianni JA. The Prion Diseases. Journal of Geriatric Psychiatry and Neurology 2010; 23(4): 277-298. (PMID: 20938044)
  10. Büeler H, Fischer M, Lang Y et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992; 356(6370): 577-582. (PMID: 1373228)
  11. Büeler H, Aguzzi A, Sailer A et al. Mice Devoid of PrP Are Resistant to Scrapie. Cell 1993; 73(7): 1339-1347. (PMID: 8100741)
  12. Sailer A, Büeler Hm Fischer M et al. No propagation of prion in mice devoid of PrP. Cell 1994; 77(7): 967-968. (PMID: 7912659)
  13. Prusiner SB. Prions. Proceedings of the National Academy of Science USA 1998; 95(23): 13363-13383. (PMID: 9811807) 
  14. Bernardi L and Bruni AC. Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-terminal vs. N-terminal Domain, a Review. International Journal of Molecular Sciences 2010; 20(14): 3606. (PMID: 31340582)
  15. Zahn R, Liu A, Lührs T et al. NMR solution structure of the human prion protein. Proceedings of the National Academy of Sciences USA 2000; 97(1): 145-150. (PMID: 10618385)
  16. Wang L-Q, Zhao K, Yuan H-Y et al. Cryo-EM structure of an amyloid fibril formed by full-length human prion protein. Nature Structural and Molecular Biology 2020; 27(6): 598-602. (PMID: 32514176)
  17. Chen C and Dong X-P. Epidemiological characteristics of human prion diseases. Infectious Diseases of Poverty 2016; 5(1): 47. (PMID: 27251305)
  18. Aguzzi A, Baumann F, Bremer J. The prion’s Elusive Reason for Being. Annual Review of Neuroscience 2008; 31: 439-477. (PMID: 18558863)
  19. Alpers M and Rail L. Kuru and Creutzfeldt-Jakob disease: clinical and aetiological aspects. Proceedings of the Australian Association of Neurologists 1971; 8: 7-15. (PMID: 5005124).
  20. Mead S, Stumpf MP, Whitfield J et al. Balancing selection at the prion protein gene consistent with prehistoric kuru-like epidemics. Science 2003; 300(5619): 640-643. (PMID: 12690204)
  21. Bruce ME, Will RG, Ironside RG et al. Transmission to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 1997; 389(6650): 498-501. (PMID: 93333239)
  22. Cuillé J and Chelle PL. Experimental transmission of trembling to the goat. CR Seances Academy of Sciences 1939; 208: 1058-1060.
  23. Gajdusek DC, Gibss CJ and Alpers M. Experimental Transmission of a Kuru-like Syndrome to Chimpanzees. Nature 1966; 209: 794-796 (PMID: 5922150)
  24. Gibbs CJ, Gajdusek DC, Asher DM et al. Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 1968: 161(3839): 388-389. (PMID: 5661299)
  25. Prusiner SB, McKinley MP, Growth DF et al. Scrapie agent contains a hydrophobic protein. Proceedings of the National Academy of Sciences 1981; 78(11): 6675-6697. (PMID: 6273882)
  26. Bolton DC, McKinley MP, Prusiner SB et al. Identification of a protein that purifies with the scrapie protein. Science 1982; 218(4579): 1309-1311. (PMID: 6815801)
  27. Oesch B, Westway D, Wälchli M et al. A cellular gene encodes scrapie PrP 27-30 protein. Cell 1985; 40(4): 735-746. (PMID: 2859120)
  28. Mead S and Reilly MM. A new prion disease: relationship with central and peripheral amyloidosis. Nature Reviews Neurology 2015; 11(2): 90-97. (PMID: 25623792)