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Prions cause diseases in mammals
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Scrapie is a disease caused by an infective agent made of protein (a prion).
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Kuru is a human neurological disease caused by prions. It may be caused by eating infected brains.
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The protein responsible for scrapie exists in two forms, the wild-type noninfectious form PrPC which is susceptible to proteases, and the disease-causing form PrPSc which is resistant to proteases.
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The neurological disease can be transmitted to mice by injecting the purified PrPSc protein into mice.
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The recipient mouse must have a copy of the PrP gene coding for the mouse protein.
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The PrPSc protein can perpetuate itself by causing the newly synthesized PrP protein to take up the PrPSc form instead of the PrPC form.
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Multiple strains of PrPSc may have different conformations of the protein.
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Prion diseases have been found in sheep and Man, and, more recently, in cows. The basic phenotype is an ataxia
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a neurodegenerative disorder that is manifested by an inability to remain upright. The name of the disease in sheep, scrapie,
reflects the phenotype: the sheep rub against walls in order to stay upright. Scrapie can be perpetuated by inoculating sheep with tissue
extracts from infected animals. The disease kuru was found in New Guinea, where it appeared to be perpetuated by
cannibalism, in particular the eating of brains. Related diseases in Western populations with a pattern of genetic transmission include
Gerstmann-Straussler syndrome; and the related Creutzfeldt-Jakob disease (CJD) occurs sporadically. Most recently, a disease resembling
CJD appears to have been transmitted by consumption of meat from cows suffering from "mad cow" disease (634).
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When tissue from scrapie-infected sheep is inoculated into mice, the disease occurs in a period ranging from
75-150 days. The active component is a protease-resistant protein. The protein is coded by a gene that is normally expressed in brain. The
form of the protein in normal brain, called PrPC, is sensitive to proteases. Its conversion to the resistant form, called PrpSc,
is associated with occurrence of the disease. The infectious preparation has no detectable nucleic acid, is sensitive to UV
irradiation at wave lengths that damage protein, and has a low infectivity (1 infectious unit / 105 PrPSc
proteins). This corresponds to an epigenetic inheritance in which there is no change in genetic information, because normal and diseased cells
have the same PrP gene sequence, but the PrPSc form of the protein is the infectious agent, whereas PrPC is harmless (383; 384; 385; for review see 203).
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The basis for the difference between the PrPSc and PrpC
forms appears to lie with a change in conformation rather than with any covalent alteration. Both proteins are glycosylated and linked to the
membrane by a GPI-linkage. No changes in these modifications have been found. The PrPSc form has a high content of ß sheets, which is absent from the PrPC form.
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Figure 23.47
A PrpSc protein can only infect an animal that has the same type of endogenous PrPC protein.
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The assay for infectivity in mice allows the dependence on protein sequence to be tested. Figure 23.47 illustrates the results of some critical experiments. In the normal situation, PrPSc
protein extracted from an infected mouse will induce disease (and ultimately kill) when it is injected into a recipient mouse. If the PrP
gene is "knocked out," a mouse becomes resistant to infection. This experiment demonstrates two things. First, the endogenous protein is
necessary for an infection, presumably because it provides the raw material that is converted into the infectious agent. Second, the cause
of disease is not the removal of the PrPC form of the protein, because a mouse with no PrPC survives normally: the disease is caused by a gain-of-function in PrPSc (386).
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The existence of species barriers allows hybrid proteins to be constructed to delineate the features required
for infectivity. The original preparations of scrapie were perpetuated in several types of animal, but these cannot always be transferred
readily. For example, mice are resistant to infection from prions of hamsters. This means that hamster-PrP
Sc cannot convert mouse-PrPC to PrPSc. However, the situation changes if the mouse PrP
gene is replaced by a hamster PrP gene. (This can be done by introducing the hamster PrP
gene into the PrP knockout mouse.) A mouse with a hamster PrP gene is sensitive to infection by hamster
PrPSc. This suggests that the conversion of cellular PrPC protein into
the Sc state requires that the PrPSc and PrPC proteins have matched sequences.
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There are different "strains" of PrPSc, which are distinguished by characteristic incubation periods upon
inoculation into mice. This implies that the protein is not restricted solely to alternative states of PrPC and PrPSc,
but that there may be multiple Sc states. These differences must depend on some self-propagating property of the protein other than its
sequence. If conformation is the feature that distinguishes PrPSc from PrPC, then there must be multiple conformations,
each of which has a self-templating property when it converts PrPC (636; for review see 214; 5855).
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The probability of conversion from PrPC to PrPSc is affected by the sequence of PrP. Gerstmann-Straussler syndrome in
man is caused by a single amino acid change in PrP. This is inherited as a dominant trait. If the same change is made in the mouse PrP gene,
mice develop the disease. This suggests that the mutant protein has an increased probability of spontaneous conversion into the Sc state.
Similarly, the sequence of the PrP gene determines the susceptibility of sheep to develop the disease spontaneously; the combination of amino
acids at three positions (codons 136, 154, and 171) determines susceptibility.
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The prion offers an extreme case of epigenetic inheritance, in which the infectious agent is a protein that
can adopt multiple conformations, each of which has a self-templating property. This property is likely to i
nvolve the state of aggregation of the protein (for review see 4864).
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Last Revised on September 28, 2004
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203 Prusiner, S.
(1982).
Novel proteinaceous infectious particles cause scrapie.
Science 216, 136-144.
PubMed
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214 Prusiner, S. B. and Scott, M. R.
(1997).
Genetics of prions.
Annu. Rev. Genet. 31, 139-175.
PubMed Journal
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4864 Wickner, R. B., Edskes, H. K., Roberts, B. T., Baxa, U., Pierce, M. M., Ross, E. D., and Brachmann, A.
(2004).
Prions: proteins as genes and infectious entities.
Genes Dev. 18, 470-485.
PubMed
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5855 Chien, P., Weissman, J. S., and DePace, A. H.
(2004).
Emerging principles of conformation-based prion inheritance.
Annu. Rev. Biochem. 73, 617-656.
PubMed
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383 McKinley, M. P., Bolton, D. C., and Prusiner, S. B.
(1983).
A protease-resistant protein is a structural component of the scrapie prion.
Cell 35, 57-62.
PubMed Journal
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384 Oesch, B. et al.
(1985).
A cellular gene encodes scrapie PrP27-30 protein.
Cell 40, 735-746.
PubMed Journal
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385 Basler, K., Oesch, B., Scott, M., Westaway,
D., Walchli, M., Groth, D. F., McKinley, M. P., Prusiner, S. B., and
Weissmann, C. (1986). Scrapie and cellular PrP isoforms are
encoded by the same chromosomal gene. Cell 46, 417-428.
PubMed Journal
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386 Bueler, H. et al.
(1993).
Mice devoid of PrP are resistant to scrapie.
Cell 73, 1339-1347.
PubMed Journal
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634 Hsiao, K. et al.
(1989).
Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome.
Nature 338, 342-345.
PubMed Journal
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636 Scott, M. et al.
(1993).
Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes.
Cell 73, 979-988.
PubMed Journal
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© Jones and Bartlett Publishers (2007)
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