What are prions? Originally thought to be viral mediators of disease that were described as transmissible encephalopathies, spongiform encephalopathies and slow virus diseases, prions, (proteinaceous infectious particles) have been determined to be misfolded, protease resistant proteins which can mediate transmission of disease.
Prions have been implicated in a quartet of human diseases, specifically kuru, Creutzfeldt-Jakob disease,(CJD), Gerstmann-Straussler-Scheinker, (GSS) disease, and fatal familial insomnia, (FFI). In sheep, scrapie is believed to be caused by prions and Bovine Spongiform Encephalopathy is a prion disease in cattle.
Stanley Prusiner won the Nobel Prize in 1997 for first proposing the remarkable hypothesis that these prion diseases were caused by misfolded proteins, and furthermore, elucidating the gene and a mechanism by which the misfolded wild type protein might bring about the amyloid plaques observed clinically. The seminal paper in which some of this information was published is available here.
This is the third figure from the report, Molecular Biology of prion diseases. Prusiner, SB, Science 1991; 252; 1515-1522. Figure 3a depicts the structure of PrPc or the wild type PrP prion protein derived from NMR data. Figure 3c is the expected structure of the PrPSc, the misfolded, protease resistant, infectious disease causing molecule.
1738: First clinical manifestation of scrapie described.
1955: Vincent Zigas begins clinical study of kuru in Papua New Guinea
1956: D. Carleton Gajdusek begins investigation of kuru.
1959: WJ Hallow observes the similarity between kuru and scrapie.
1962: H.B. Parry believed that scrapie can be eradicated by breeding methods.
1965: First chimpanzees injected with brain extracts of both kuru and CJD patients developed similar symptoms to
the respective diseases.
1982: Stanley Prusiner et al: develop animal model for studying prion infectivity.
1986: BSE epidemic in England. Believed to arise from contaminated feed.
1988: N. Hunter observes fibrils in BSE infected cows that are similar to scrapie protein.
1990: J. Hope determines two alleles of protein gene linked to scrapie in sheep.
1991: Stanley Prusiner elucidates the molecular biology of prion proteins.
1993: T.G.F. Esmonde determines possible links to CJD caused from BSE.
1997: Stanley Prusiner wins Nobel Prize for work in prion concept.
Scrapie has been known for as long as man has been herding sheep with the first clinical manifestation described in 1738. H.B. Parry, believed that scrapie was a genetic disease and could be eradicated with appropriate breeding controls. Parry H.B., Scrapie: a transmissible and hereditary disease of sheep. Heredity 1962; 17:75-105. He also believed that transmission by inoculation to be of importance primarily for laboratory studies but not for communicable infection in nature. Studies of the open reading frame of the PrP gene in Suffolk sheep in American have determined argued that susceptibility in Suffox sheep to scrapie is governed by the PrP codon 171 polymorphism. Goldmann, W., Hunter N., Foster, J.D., Salbaum J.M., Beyreuther K., Hope J., Two alleles of a neural protein gene linked to scrapie in sheep. Proc Natl Acad Sci USA 1990;87:2476-2480. There have been no epidemics of scrapie in sheep, however, natural scrapie is readily spread within flocks.
Unlike scrapie, in 1986 there was and epidemic of a previously unknown disease that developed in herds of cattle in England. Originally called Bovine Spongiform Encephalopathy but it is commonly called mad cow disease. BSE was shown to be a prion disease by elucidation of protease resistant PrP, (prion) protein in brains of ill cattle. Hope, J., Reekie, L.J.D., Hunter, N., Fibrils from brains of cow the new cattle disease containing scrapie associated protein. Nature 1988;336:390-392.
Based upon epidemiological evidence, the BSE epidemic in England is proposed to have been derived from the process by which MBM, a nutritional supplement, is made. Specifically, the rendering process by which lipid rich fractions are isolated from sheep and cattle offal might protect misfolded scrapie prions from the sheep offal from being inactivated by the steam used in the rendering process. Since 1988, the use of dietary protein supplements derived from sheep and cattle offal has been prohibited in the UK, however, it is unknown whether or not this will actually affect the incident of BSE in England as nearly half of the BSE cases in the UK have occurred in herds where only one cow is affected, and multiple cases of BSE in single herds is infrequent. Wilesmith J.W., Wells, G.A.H., Cranwell, M.P., Ryan, J.B.M. Bovine spongiform encephalopathy: epidemiological studies. Vet Rec 1988; 123:638-644.
Other lines of evidence against the possibility that the BSE epidemic might have been caused by scrapie prions in the MBM feed are that bovine PrP differ from sheep PrP at seven or eight residues. It has not yet been established if scrapie prions transferred into cattle brains can initiate infection. Goldman,W., Hunter, N., Martin, T., Dawson, M., Hope, J. Different forms of the PrP genes have five or six copies of a short, G-C rich element within the protein coding exon. J Gen Virol 1991;72:201-204.
It is still unknown whether or not scrapie, initially implicated in CJD, or BSE prion can cause disease in humans, although two farmers with BSE afflicted cattle have died of CJD in 1993. Sawcer, S.J., Yuill, G.M., Esmonde, T.G.F., et al. Creutzfeldt-Jakob disease in an individual occupationally exposed to BSE. Lancet 1993;341:642.
Kuru and other Human Prion Diseases:
Both images from Sperling Biomedical Foundation page. Figure 1, the native confomer predicted from NMR spectra data and the proposed PrPSc human prion protein. Figure 2 shows the human mutations associated with all human prion diseases superimposed on the hamster PrPc prion gene product.
Kuru was first seen by a foreigner to Papua New Guinea in 1954 by an Australian patrol officer who observed a young Fore tribe girl who was shaking violently and her head was jerking savagely from side to side. In 1955 Vincent Zigas, a district medical officer in the Fore tribe region began official medical study. However, after conventional methods for isolating the causative agent failed, Dr. Zigas discontinued his research. Subsequently in 1956, a researcher from Harvard, D. Carleton Gajdusek set off for Papua New Guinea to study kuru. Dr. Gajdusek originally considered viral menigoenphalitis but there where no clinical signs or symptoms to support this. He then considered an environmental toxin but found no evidence. Upon assessment of geological incident of disease, he isolated a region, approximately 35 by 25 miles across where the highest incident of disease occurred. Furthermore, Fore women from this area, who married into other tribes carried the disease with them, with their children having a higher prevalence of the kuru disease. Dr. Gajdusek then considered a possible genetic linkage for predilection to the disease. However, the tools of the day made it impossible for Dr. Gajdusek to continue his investigations.
Then in 1959 a veterinary surgeon WJ Hallow commented in Lancet upon the similarities between kuru and sheep scrapie. Dr. Gajdusek returned to Papua New Guinea and sent necropsy samples to Bethesda to be intracranially inoculated into chimpanzees. In 1965 the first batch of chimpanzees from this study developed symptoms and signs similar to kuru.
However, two anthropologist, Robert and Shirley Glasse determined that kuru was only 50 years old. Also, cannibalism had been uncommon in the Fore people until 1915 where they began to eat human flesh at a Kamano feast. From this point cannibalism began to be associated with the funeral rituals. After putrefying for three or four days, the body was baked and totally consumed. The mother and brother ate the brains while the other men of the tribe typically forewent the meal as they superstitiously believed it would hamper their fighting ability. With the cessation of cannibalism, the incident of kuru significantly decreased in the Fore people.
At the same time as the kuru innoculated chimpanzees developed clinical signs of kuru, other chimpanzees were inoculated with brain extracts from diseased CJD patients. These chimps also developed CJD signs and symptoms. With the pathological similarity of kuru, scrapie and CJD, and transfere of the agent to animal models, multiple groups began to search for the infectious agent.
In 1982 Stanley Prusiner developed a Syrian hamster model for studying the infectivity and onset of disease of prion proteins and mutations. Prusiner, S.B., Cochran, S.P., Groth, D.F., Downey, D.E., Bowman, K.A., Martinez, H.M. Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol 1982;11:353-358. From this assay and subsequent elucidation of the prion gene continuing work has been aimed at elucidating the precise pathology of prion diseases.
Initially the prion gene knockout mice were without abnormal phenotypes. Lipp, H.P., Stagliar-Bozicevic, M., Fischer, M., Wolfer, D.P., A 2-year longitudinal study of swimming navigation in mice devoid of prion protein: no evidence for neurological anomilies or spatial learning impairments. Behavioral Brain Research; 1998 Sept. 95(1):47-54. However further experiments showed increased susceptibility to prion diseases with specific prion gene deletions or mutations. In addition, specific perceptual deficiencies and lesions in the brain have been elucidated in the prion knockout mice. Fischer, M., Rulicke, T., Raeber, A., Sailer, A., Moser, M., Oesch, B., Brandner, S., Aguzzi, A., Weissman, C., Prion protein (PrP) with amino proximal deletions restores susceptibility of PrP in mice to scrapie. EMBO J. 1996, Mar. 15 15(5):1255-64. Shmerling, D., Heggi, I., Fischer, M., Blattler, T., Brandner, S., Gotz, J., Rulicke, T., Flechsig, E., Cozzio, A., von Mering, Expression of amino terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions, Cell, 1998 Apr. 17 93(2)203-214.
As prions do not contain nucleic acids, they are clearly not viruses. The precise nature of their infectivity is still some matter of dispute. However, it would appear from work already cited, that the specific mutations in the prion gene permits the folding of a new conformation that is protease resistant. This new conformation then has the capacity over time to associate with other misfolded proteins. The kinetics of these associations predict the interactions are not cooperative, this is to say that the misfolded prion protein does not actively recruit other misfolded prion gene products for form multimers. The data seems rather to define a slow process by which the occasionally misfolded prion protein will exist in the cell for an extended period of time, after which another randomly misfolded prion protein will associate with the first. Subsequently, as multimers of the misfolded prion proteins associate, they have a greater statistical chance of associating with other misfolded prion proteins. It is unknown as to whether or not the large oligomers of the misfolded prion can promote misfolding of normally expressed prion products. Although there is no evidence yet for this activity, it is still an attractive hypothesis. Subsequently, large multimers or amyloid plaques may form that may cause lesions or other cellular damage. In human CJD, amyloid plaques are a hallmark of progressive disease whereas in sheep and cows neural tissue that is full of holes like a sponge are more often found.
Interestingly, inherited CJD have mutations that may reflect the spontaneously occurring mutations in the non inherited disease. However, these inherited mutations do not seem in decrease the time course of the disease, just increase the susceptibility/probability of acquiring the disease.
At this time multiple labs, who's work I've cited and partially described are actively investigating the nature of prion diseases and the mechanisms by which misfolding may increase the propensity to form plaques, or cause specific neural tissue destruction.
Some of the current labs investigating prions:
Prusiner, S.B.; Knock-outs in mice, kinetics of disease, and mechanisms for disease progression.
Weissman C.; Specific mutations in prion gene that effect kinetics and susceptibility to disease.
Von Mering A,; Mutations that bring about specific types of lesions or disease.
Wolfer D.P.; Neural abnormalities in prion knock-out models.
Page Designer: John B. Mumm in Dr. Robert Siegels' Humans and Viruses Class. Works cited are in italics. I also made significant use of Fields Virology, Third Edition, Chapter 3, Robert A. Lamb, Robert M. Krug. Orthomyxovirdae: The Viruses and Their Replication.