Eric M. Nicholson Jürgen A. Richt
National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, Iowa, U.S.A.
Prions are proteinaceous infectious particles, and in the most general of terminology they are chromosomally encoded proteins that have undergone a conformational change such that the new altered conformation is capable of causing a conformational change in additional molecules of the normal prion protein. They are the causative agents of a class of progressive and ultimately fatal neurodegenerative diseases known collectively as transmissible spongiform encephalopathies (TSEs). In all TSEs the normal cellular isoform of the prion protein (PrPC), a protein of unknown function, undergoes conversion to a protease-resistant disease-associated infectious isoform (PrPRes). This disease-associated conformation of the protein is also referred to as PrPSc (denoting the association with scrapie) and PrPd (indicating the disease-associated form).
The concept of an infectious protein contradicts much of what is typically understood about infectious diseases. PrPRes recruits and converts PrPC to the disease-causing PrPRes conformation, in what is referred to as the protein-only hypothesis. While controversy has surrounded the protein-only hypothesis, recent results indicate that bacterially derived recombinant PrP may be folded to an infectious conformation in vitro providing strong support for the concept of an infectious protein. The PrPC to PrPRes conversion process is believed to be purely structural, where the a-helix-rich PrPC adopts the PrPRes conformation, containing less a-helix structure and a substantially higher p-sheet content. It is this structural change that underlies the disease process, and gives rise to enhanced resistance to proteolytic hydrolysis, an important aspect of most current diagnostic methods.
The prion protein is present in all mammals with significant sequence homology between species. PrP is encoded by the Prnp gene as an approximately 254-amino acid polypeptide; following processing at both the amino and carboxyl termini, PrP consists of an approximately 209-amino acid protein. The N-terminal region of PrP encompasses an octarepeat region that has been, based upon studies of recombinant PrP, determined to be largely unstructured in solution.
After limited proteolysis of PrPRes, it is this N-terminal region that is cleaved from the ^140-amino acid protease-resistant PrP fragment known as PrP 27-30.
Prions accumulate in an infected host eventually leading to neurodegeneration and disease. Like other infectious agents, prions exist in different strains. Terminology surrounding TSE strains can be confusing, with the term "strain'' being used to refer to both different TSEs [chronic wasting disease (CWD), scrapie, bovine spongiform encephalopathy (BSE), etc.] and to indicate differences within a given TSE. Strains of TSEs are defined by varied host range, clinical presentations, and incubation times and may give rise to different vacuolation patterns, staining patterns by immunohistochemical analysis, and/or proteolytic cleavage sites and glycoform profiles as observed on a Western blot. The phenomenon of prion strains is difficult to rationalize if PrPRes is composed only of host-derived protein. In the context of the protein-only hypothesis strains must arise from different conformations of PrPRes.
A notable feature of prion diseases is a lack of detectable immune responses and inflammation during the course of a prion infection. This is likely a result of the host-encoded nature of the accumulated protein deposits failing to be recognized by the host immune system.
Scrapie in sheep and goats, transmissible mink encephalopathy, CWD in cervids, feline spongiform encephalopathy, exotic ungulate encephalopathy, and BSE are the TSEs that have been identified in wild and domestic animals. The interest in these diseases is great with respect to animal health, the overall safety of the human food supply, and the global economy. For the purposes of this review we will focus on scrapie, CWD, and BSE.
Scrapie is a fatal neurodegenerative disorder caused by prions, and was the first spongiform encephalopathy for which transmissibility was demonstrated. The disease was initially reported in England in 1732, and to date there is no evidence supporting the transmis-sibility of scrapie to humans. In general, the clinical signs begin with impaired social behavior, restlessness, and nervousness. As the disease progresses, the condition of the animal will deteriorate and there may even be a change in fleece color. The scratching behavior associated with the name of the disease may result in loss of wool in a small area or perhaps even an entire side of the body. Ultimately, ataxia may become pronounced, and the sheep may become highly agitated by even minor stress. In a clinically presenting animal, common neuropathologic lesions in the brain include the formation of cytoplasmic vacuoles and reactive astrogliosis.
Even prior to the development of our understanding of scrapie as a prion disease it was clear that susceptible and resistant phenotypes existed in the sheep popu-lation. Ultimately it was determined that the DNA sequence of Prnp is variable (polymorphic) at several sites in the gene; this is known as an allele. Depending upon the specific DNA sequence of each allele, variations in the amino acid sequence of the prion protein may result as well. In sheep, amino acid changes at codons 136, 154, and 171 of the cellular prion protein have been associated with susceptibility/resistance to scrapie. The V136R154Q171 allele is associated with high susceptibility and the A136R154R171 allele with resistance to scrapie. In sheep breeds where the VRQ allele is rare, ARQ/ARQ is the genotype that is most susceptible to scrapie, while animals that are ARQ/ ARR or ARR/ARR are rather resistant. Sheep breeding programs are being undertaken to enhance scrapie resistance via increased prevalence of RR171 genotypes. The successfulness of such breeding programs in terms of scrapie eradication has yet to be determined.
Chronic wasting disease is a prion disease of cervids. White-tailed deer, mule deer, moose, and elk in free as well as captive populations have been found to be infected. The disease was first recognized in a captive population of mule deer at a wildlife research facility in the 1960s, although the identification of the disease as a TSE did not occur until the late 1970s. In contrast to other TSEs, CWD can be spread horizontally with no defined route of transmission determined to date. The most widely accepted hypothesis at this time is that CWD may have arisen from scrapie. It is worth noting that experimental transmission of scrapie into elk is indistinguishable from CWD, with currently available experimental methods.
Like scrapie there appears to be a polymorphism associated with relative resistance/susceptibility in elk. A single-site polymorphism has been identified at position 132, where M is associated with susceptibility and L with relative resistance. The Prnp genotype influence on susceptibility to CWD in deer is less clear.
Testing of hunter-killed animals indicates that between ~1% and 20% of animals in free-ranging deer populations in endemic areas may be infected. The most prominent clinical sign of CWD is the basis for its name, eventual emaciation. Some animals may show hypersalivation and difficulty swallowing; elk, in particular, exhibit ataxia and tremors. The known geographic range of CWD appears to be growing along migration routes for the affected species and through shipments of captive cervids. At this time, Montana, Wyoming, South Dakota, Minnesota, Wisconsin, Colorado, Nebraska, Kansas, Oklahoma, New York, West Virginia, as well as Alberta and Saskatchewan have all had confirmed cases of CWD in either captive or wild cervid populations. Cases of CWD have been diagnosed in South Korea in deer and elk imported from Canada. The fact that freeranging animals are infected with CWD and the apparent capability of CWD to be horizontally transmitted indicates that the prevalence of the disease may increase for the foreseeable future.
While scrapie has been known to exist in their respective host populations for many years and elicited little or no concern among the general population, this has not been true for BSE. Shortly after the first identification of what has ultimately been termed BSE in British cattle in 1986, it was recognized that a new neurologic disease of cattle had arisen with striking similarities to scrapie. Clinical signs include apprehensive or perhaps even aggressive behavior, ataxia, and abnormal responses to environmental stimuli.
Epidemiological studies suggest that dietary protein supplements, in particular meat and bone meal (MBM), were the source of the outbreak in Great Britain and that this occurred as a result of altered rendering practices that began in the late 1970s. The recognition of this resulted in a ruminant feed ban preventing the feeding of ruminant-derived protein material to ruminants in the U.K. in 1988. Similar measures have been adopted in other nations, including the U.S.A. and Canada in 1997. Additional prohibitions have included the ban of certain bovine tissues that contain detectable levels of BSE from entering the human food chain; a measure intended to prevent the theoretical transmission of BSE to humans. These tissues have been termed specified risk material (SRM).
The prohibition of SRM in the human food supply has undoubtedly limited human exposure, but the occurrence of a new human TSE termed "variant Creutzfeld-Jakob Disease'', occurring about 10 years after the initial BSE cases in the U.K., indicates that the protective measures were either incomplete or implemented too late. It is worth noting that despite the apparent linkage to scrapie, various scrapie isolates from sheep can be transmitted to cattle, but that the pathology differs from both BSE in cattle and scrapie in sheep. In addition, experimental transmission of scrapie to cattle via the oral route has not been success-ful. A recently published hypothesis suggests that BSE may have arisen from a human TSE.
Bovine spongiform encephalopathy has occurred in other European countries, but with much lower reported incidences than in the U.K. Indigenous cases have also occurred in Japan, Israel, Canada, and the U.S.A. The lower rates of incidence in these countries relative to the U.K. likely occur owing to earlier implementation of a ruminant to ruminant feed ban with respect to initial cases, a higher sheep to cattle ratio in the rendered MBM in the U.K., and differences in the feeding practices in different countries.
This review summarizes the basic concepts and terminology of TSE biology with particular attention paid to the more commonly occurring TSEs. It is important to note that while the basic principles remain constant across TSEs, significant differences exist between various TSE agents in different species necessitating study in natural hosts. Research on prion diseases is a rapidly evolving field involving scientists from a wide spectrum of basic and applied disciplines; ultimately, many aspects of prion diseases are still unknown, inconclusive, and sometimes even controversial.
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