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ScienceWeek
EPIDEMIOLOGY: NEW VARIANTS OF SCRAPIE
The following points are made by M. Baylis and K.M. Mcintyre (Nature 2004 432:810):
1) Scrapie is a fatal brain disease of sheep and goats and is part of the transmissible spongiform encephalopathy (TSE) family. This family also includes chronic wasting disease of deer, bovine spongiform encephalopathy (BSE) in cattle, and variant Creutzfeldt-Jakob disease in humans. Unlike these relative newcomers, however, scrapie has been present for more than 250 years in European sheep flocks and has spread to many other parts of the world[1].
2) In the 1990s, a proportion of sheep were found to be genetically resistant to scrapie[2] and, consequently, many countries have established programs to create disease-resistant national flocks by selective breeding. This new and unusual approach to disease control needs urgent reappraisal, however, as recent discoveries in Europe suggest that the selected sheep might be susceptible to strains of the disease that arise in the future. Atypical forms of scrapie have been reported in "resistant" sheep in Germany[3], Portugal[4] and France[5]. And a recently discovered strain of scrapie, called Nor98, is now being detected in several European countries. Moum et al (2004) have demonstrated that this strain primarily affects sheep that rarely succumb to conventional scrapie; conversely, typically "susceptible" sheep seem to be unaffected.
3) Whether or not a sheep can succumb to scrapie is determined by the sequence of amino acids that form its prion protein, which is encoded by its PrP gene. Five variants (called haplotypes) of the PrP gene are known to affect susceptibility. Sheep that inherit the ARR haplotype from both parents (ARR/ARR) have the greatest resistance to conventional scrapie[2]. Conversely, sheep inheriting the VRQ haplotype from both parents (VRQ/VRQ) are extremely susceptible[2] to conventional scrapie and, in some infected flocks, all such animals would be expected to die from the disease. Fifteen types of sheep are definable on the basis of the pair of PrP haplotypes inherited from their parents.
4) A fundamental assumption of selective breeding programs is that "resistant" sheep really are, and will remain, resistant to scrapie. But this assumption is now being challenged by the new findings[3-5] emerging from mainland Europe. In 2002, many EU member states began large-scale testing of sheep in abattoirs for scrapie, using BSE-detection methods. This surveillance has revealed that scrapie is more widespread than previously believed. It has also uncovered "atypical" types. These differ from conventional scrapie in several ways, such as the pattern of deposition in the brain of the abnormal form of the prion protein.
References (abridged):
1. Detwiler, L. A. & Baylis, M. Rev. Sci. Tech. OIE 22, 121-143 (2003)
2. Hunter, N. Trends Microbiol. 5, 331-334 (1997)
3. Buschmann, A. et al. J. Gen. Virol. 85, 2727-2733 (2004)
4. Orge, L. et al. J. Gen. Virol. 85, 3487-3491 (2004)
5. Report on the Monitoring and Testing of Ruminants for the Presence of Transmissible Spongiform Encephalopathy (TSE) in the EU in 2003, Including the Result of the Survey of Prion Protein Genotypes in Sheep Breeds. Rep. 04-D-420525 (European Commission Health & Consumer Protection Directorate-General, Brussels, 2004)
Nature http://www.nature.com/nature
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BOVINE SPONGIFORM ENCEPHALOPATHY: ANALYSIS OF A POTENTIAL EPIDEMIC IN BRITISH SHEEP
The following points are made by R.R. Kao et al (Science 2002 295:332):
1) Bovine spongiform encephalopathy (BSE) in the UK was spread through feed containing meat and bone meal contaminated with BSE-infected animal material. Sheep in the UK were also fed the same materials, and it is known that sheep can be infected with BSE by the oral route. No field cases of sheep BSE have been observed, but it has been a concern for a number of years, partly because sheep are the natural hosts of scrapie, a transmissible spongiform encephalopathy that has clinical signs indistinguishable from BSE.
2) Because there is a theoretical possibility that the British national sheep flock is already infected with BSE, the authors examined the extent of a putative epidemic. An age cohort analysis based on numbers of infected cattle, dose responses of cattle and sheep to BSE, levels of exposure to infected feed, and number of BSE-susceptible sheep in the UK showed that at the putative epidemic peak in 1990, the number of cases of BSE-infected sheep would have ranged from fewer than 10 to about 1500. The model predicts that fewer than 20 clinical cases of BSE in sheep would expected in 2001 if maternal transmission occurred at a rate of 10 percent. Although there are large uncertainties in the parameter estimates, all indications are that current prevalence is low. However, a simple model of flock-to-flock BSE transmission demonstrates that horizontal transmission, if it has occurred, could eventually cause a large epidemic.
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CELL BIOLOGY: ON THE INFECTIVITY OF PRIONS
The following points are made by Daniel C. Masison (Nature 2004 429:37):
1) Alzheimer's disease, type II diabetes, and prion diseases --mad cow disease being the most notorious -- are all characterized by the accumulation of misshapen proteins into aggregates in various parts of the body. Of these disorders, however, only prion diseases are infectious. Clumps of prion proteins alone are thought to be the infectious agent in such diseases, implying that infectivity is a special property of these proteins. But despite extensive studies, researchers have discovered little more than this about the basis for the transmissibility of prions. However, by swapping portions of one yeast protein with those of another, Osherovich et al(1) have reported hints to a possible mechanism.
2) Yeast prions are known to be transmitted between yeast strains, along with the cellular cytoplasm, during cell fusion, and from mother to daughter yeast cells during cell division. Two events are necessary to ensure that these protein clumps continue to be transmitted. First, they must grow, by causing normal prion proteins to take on a warped shape that favors their aggregation. And second, they must divide, generating new prion particles that can be passed to a new cell. This division, or replication, is thought to involve small clumps breaking off from the main mass, with the help of a "chaperone" molecule(2,3). Transmission then probably occurs by diffusion. Thus, transmission efficiency is related to the efficiency of prion replication.
3) Most proteins do not replicate in this way, so what enables a prion protein to do so? To find out, Osherovich et al(1) looked at [PSI+] -- the name given to the prion form of the yeast protein Sup35, which normally functions in the synthesis of other proteins. The ability of Sup35 to form a prion depends on a region at one end of the protein, the amino-terminal end. This well-studied "prion domain" is rich in glutamine and asparagine amino acids -- a property shared by all three confirmed yeast prion proteins. It also contains five-and-a-half repeats of a sequence of nine amino acids, which resemble five repeats that are seen in the only known mammalian prion protein, PrP. The glutamine/asparagine-rich region contributes to species specificity: the prion domains of Sup35 from different yeast species, which have different glutamine/asparagine-rich sequences, can aggregate in the same cell, but do so independently of one another(4). The role of the repeats has been less clear, although they are involved in [PSI+] propagation.
4) Osherovich et al(1) uncovered a role for the repeats while studying the prion-related properties of a region in New1, a putative prion protein that they had previously identified(4) while searching the yeast genome for asparagine-rich sequences. In addition to an asparagine-rich region, New1 has one-and-a-half Sup35-like repeats. As the protein has no known function, it is difficult to show that it can behave as a prion (such a demonstration requires a protein's normal function to be disrupted by the prion form). But the authors did obtain some evidence for this when they created a new prion(4) -- which they named [NU+] -- by replacing the entire prion domain of Sup35 with that of New1. Osherovich et al have demonstrated that the asparagine-rich stretch alone of [NU+] causes aggregation -- but that stable transmission of this prion also requires the repeats.(5)
References (abridged):
1. Osherovich, L. Z., Cox, B. S., Tuite, M. F. & Weissman, J. S. PLoS Biol. 2, 0442-0451 (2004)
2. Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Science 268, 880-884 (1995)
3. Paushkin, S. V., Kushnirov, V. V., Smirnov, V. N. & Ter-Avanesyan, M. D. EMBO J. 15, 3127-3134 (1996)
4. Santoso, A., Chien, P., Osherovich, L. Z. & Weissman, J. S. Cell 100, 277-288 (2000)
5. Cummings, C. J. & Zoghbi, H. Y. Annu. Rev. Genomics Hum. Genet. 1, 281-328 (2000)
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