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Spongiform encephalopathies, or prion diseases, have captured the imaginations of scientists and non-scientists alike. These diseases are unusual because they are both heritable and transmissible. Additionally the proposed causative agent is not a living organism and doesn't even require a nucleic acid to wreak its havoc. It is merely a small, misfolded protein—one that sticks to metal and plastic, is resistant to heat, protease, and other typical sterilization methods. And, even more intriguing, this misfolded protein seems to be able to jump the species barrier to cause disease, perhaps even from cattle to humans. This online serial feature will explore prion biology and diseases, take a historical look at the history of prions, and discuss the technologies and future science coming out of current prion research. Installment I: Introduction to Prion Diseases and Biology A
Brief History of Prions |
In 1939, sheep in Scotland were vaccinated against “looping ill.” The vaccine, prepared from formaldehyde-treated sheep brain extract, contained a hidden infectious agent. This agent retained infectivity even after formaldehyde treatment, and it transmitted Scrapie, a devastating neurological disease, to 10% of the vaccinated sheep (1).
Spongiform encephalopathies are neurological diseases that
are unusual because they are both inherited and infectious. The diseases
primarily affect the central nervous system, resulting in many large vacuoles
(holes)—giving the brain the appearance of a sponge. These diseases affect a
wide variety of species including humans, cattle, cats, sheep, deer, and many
others. The diseases are not caused by a bacterium—or a virus—or anything
containing nucleic acid. They appear to be caused by nothing more than a
misfolded protein, called a prion (proteinaceous infectious only;
2). In addition, prions can apparently cross species barriers.
In 1986, BSE (bovine spongiform encephalopathy or “mad cow disease”), a prion disease of cattle was described in England (3). The symptoms in affected cattle included rapidly changed behavior, inability to stand, and reduced sensation. When the epidemic peaked in 1993, an estimated 1.2 million animals were possibly infected, and the meat of about 730,000 BSE-infected cows had entered the human food chain (3). Exports of beef from the United Kingdom were halted, and entire herds of cattle were destroyed to prevent the spread of the disease. The economic cost was huge.
Recently thousands of elk and deer in Colorado and Wisconsin have been destroyed to prevent the spread of chronic wasting disease. The impact on the hunting and tourism industries in these states, not to mention the food banks that rely on venison donations from hunters, remains to be assessed.
Among the first human spongiform encephalopathies described was KURU, a National Geographic “curiosity” limited to a distant third-world, cannilbalistic tribe—certainly not a threat to first-world inhabitants. One inherited form of human prion disease, Creutzfeldt-Jacob Disease (CJD) was described prior to 1922, but only later was it recognized as a prion-caused disease (4). Still, the inherited cases were rare and believed not to be transmissible, so the perceived threat was minimal. Then in 1996, new variant CJD (vCJD) was described based on 10 cases in Britain; scientists have now described over 100 cases of vCJD in the United Kingdom, Ireland and France. Unlike CJD or KURU however, vCJD was a different threat because it was linked to BSE in cattle.
The strain properties of vCJD, which include the pattern of tissue destruction and the disposition of clumps of protein in the nervous tissue, are very similar between vCJD of humans and BSE of cattle (4). Biochemical studies to determine the pattern of proteolytic digestion of vCJD and BSE prions indicate that they are virtually indistinguishable (4). The epidemiology of vCJD also supports a link between the disease in cattle and humans. For instance, no confirmed cases of vCJD occur in geographic areas that are free of BSE, and the highest prevalence of vCJD occurs in areas with the highest prevalence of BSE (4,5). Because the incubation period of vCJD is so long, with years between ingesting the infected meat and developing clinical symptoms (5), researchers have not definitely linked BSE with vCJD.
Prions have been found in species from yeast to humans. The human protein is a 250-amino acid, GPI-linked (glycosyphosphatidylinositol-linked) membrane protein called PrPc (cellular Prion). It is encoded by the Prn-p gene and is highly expressed in the central nervous system with lower levels of expression in immune cells and muscle. Structurally the normal protein consists of three alpha helices with a C-terminal gobular domain. Its expression in cells is highly regulated during development and is influenced by Nerve Growth Factor (1,6).
PrPsc (the pathogenic form) is identical to PrPc at the amino acid sequence level, however its secondary and tertiary structure is different. PrPsc has a high beta sheet content, is detergent insoluble, and is partially protease resistant. It is also resistant to heat and irradiation.
Very little is known about the normal cellular function of the prion protein. PrPc-null mice appear to develop normally, and they are not susceptible to disease when challenged with the disease-causing form of the protein (PrPsc; 1). PrPc has a high affinity for laminin and may be important for cell adhesion, differentiation and survival. Additionally, neurons lacking PrPc seem to be more sensitive to oxidative stress (6). Since prions are found in species from yeasts to humans, prions may play a fundamental biological role in cells, but the nature of that role is unknown.
Current thought suggests that the misfolded PrPsc acts as a template to direct normal cellular proteins to assume its pathogenic, abnormal structure. Once this has happened, the proteins lose their ability to function normally and begin to form aggregates in the nervous tissue, ultimately leading to the spongiform disease.
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