MEDICAL GRAND ROUNDS LLIAM S. WILKE, MD, EDITOR TAKE-HOME POINTS FROM EDUCATIONAL PRESENTATIONS BY CLEVELAND CLINIC FACULTY AND VISITING PROFESSORS Kuru and mad cow disease: Understanding the prion theory G. RICHARD OLDS, MD • NEW GUINEA, 1957: Chairman, Department of Medicine, MetroHealth Medical Center, Cleveland; A NEW DISEASE AMONG THE CANNIBALS Charles H. Rammelkamp Jr. Professor of Medicine, Case Western Reserve University College of Medicine; expert in geographic medicine and tropical disease. Chaired a number of committees for the World Health Organization, Shortly after World War II, stories began to circulate among colonial authorities about a • ABSTRACT strange neurologic disease affecting the Fore A preponderance of evidence indicates that (pronounced four-ay) people of the remote several neurodegenerative disorders are highlands of Papua, New Guinea, one of the caused by prions: abnormally folded proteins most isolated and primitive areas in the world. that can induce abnormal folding in other In 1957, Dr. Carleton Gajdusek began work normal protein molecules. Further, these among the Fore, which would occupy him for "infections" can cross some species barriers. many years and eventually win him the Nobel Prize in 1976.2 OR DECADES, the causative agents of dif- The disease that Gajdusek found was like ferent spongiform encephalopathies in no other he had ever seen. Victims were pre- man and animals, such as kuru, scrapie, and dominately women and children. The tribes- Creutzfeldt-Jakob disease, were a mystery. The people called the disease kuru (trembling, diseases were transmissible, but the victims shaking), because of one of its prominent signs. Prions have showed no clinical or pathological signs of Other signs were psychiatric changes, inappro- forced us to infection. Cultures of victims' brains revealed priate affect (including inappropriate laugh- nothing. Further, usual sterilization procedures ter), and cerebellar ataxia. Dementia occurred rethink our did not destroy the agents' infectivity. only late in the disease, if at all. Once the signs ideas about The implication of these findings seemed appeared, the disease invariably progressed preposterous: the agent consisted of protein within months to complete debilitation and infectious alone, with no nucleic acid at all. Such a the- death.3 agents ory would violate all known concepts of infec- The brains of the victims, preserved in tion. Yet it was precisely this theory that Dr. formaldehyde and sent to the NIH for patho- Stanley Prusiner proposed in 1982,1 and for logic analysis, showed changes similar to which he was awarded the Nobel Prize in 1997. those produced by scrapie, a disease of sheep. With the recent controversy in England Specifically, the cerebellums contained over bovine spongiform encephalopathy florid amyloid plaques and spongiform (BSE), better known as mad cow disease, and changes—literally, spongelike holes where its apparent jump to humans, there is a grow- neurons used to be.4 ing understanding that prions are not just a Studies in chimpanzees confirmed what medical curiosity, but a potentially grave pub- epidemiologic studies suggested: the disease lic health threat. was transmissible.5 Extracts from the brains of This brief article presents a short history of human victims, injected into chimps, resulted the development of the prion theory of disease, in a disease very much like the human disease, an overview of that theory, and some of the and extracts from the infected chimps' brains lessons that our understanding of kuru and mad could in turn induce the disease in other cow disease holds for contemporary society. chimps. Yet, as with scrapie, workers could find CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • NUMBER 6 JUNE 1998 291 Downloaded from www.ccjm.org on October 6, 2021. For personal use only. All other uses require permission. MEDICAL GRAND ROUNDS ease, and to growth hormone extracted from human cadavers.7 A..», 4~ y • •• t»V' *!«v • UNITED STATES, 1982: THE PRION THEORY PROPOSED ! • i* <* „ J - * - • r •*«»* ; y* -v. Noting that the infectious agents in kuru, - •••> « » * , ; i •• *• v « • >• • r 5. ... '.¿J ' v scrapie, and Creutzfeldt-Jakob disease were — » . Ci. • * •* - "if impervious to normal sterilization procedures, • . /" , ^ -'' * • • « V », •*; v and were not destroyed by electron radiation < *v . .. >a •»$ \ ••» or ultraviolet light at a wavelength specifical- ; / - t s «? *• * u» ly absorbed by nucleic acids, scientists began ' • yi # . * , - 4 * • '-./A, , • to develop an alternate theory, that proteins v • r * , alone were responsible for these diseases.1 In this theory, a naturally occurring pro- •HHKHiHHHilHH tein is transformed into a mutant form—a FIGURE 1. Brain tissue from a patient with Creutzfeldt-Jakob "prion"—that is then able to convert proteins disease, showing the characteristic spongiform changes. with normal three-dimensional structures to SOURCE: COURTESY OF RICHARD A. PRAYSON, MD. the mutant form, giving an infectious proper- ty to this inanimate protein. no trace of an agent, either bacterium or virus. Further, victims showed no signs of infection, Normal prion protein such as fever or adenopathy. Workers at that Within the neurons of most mammals is a pro- time speculated that kuru, scrapie, and similar tein, called prion protein (PrP). This prion diseases were caused by "slow viruses," protein, which is naturally produced in the although the actual agent eluded them. cytoplasm, has a phospholipid anchor and Gajdusek and others eventually linked kuru appears to bind to the cell membrane. to ritual cannibalism. Women and children The function of normal prion protein is ln prion comprised most of the kuru victims because unclear. Genetically engineered mice that diseases, the they, and not men, consumed the brains of their cannot produce prion protein grow and repro- family members who had died. The women duce normally. These "knockout" mice exhib- normal shared this protein meal with the small children it only subtle abnormalities, such as altered protein shape that always accompanied them. Adult men, circadian rhythms, progressive but mild atax- who ate the flesh, were largely unaffected. After ia, and decreased gamma-aminobutyric acid mutates cannibalism was eliminated in the 1960s, the (GABA)-mediated synaptic inhibition. This incidence of kuru steadily declined. latter effect suggests that prion proteins are involved in regulating GABA activity. • UNITED STATES, 1974: However, these knockout mice cannot get IATROGENIC TRANSMISSION spongiform encephalopathies when injected OF CREUTZFELDT-JAKOB DISEASE with infectious prions, providing the best evi- dence to date in support of the prion. Creutzfeldt-Jakob disease is a rare, degenera- tive neurologic disease, also characterized by Structure of normal spongiform changes in the brain (FIGURE 1), and abnormal prion protein that usually occurs sporadically in persons in The backbone of normal prion protein is their 60s, although there is sometimes a twisted into spiral shapes known as "alpha hereditary linkage. In 1974, a case occurred in helices" (FIGURE 2). In prion diseases, the nor- a middle-aged woman who had received a mal shape of the protein is transformed, struc- corneal transplant from a donor with ture, with the spiral helices stretched out into Creutzfeldt-Jakob disease.6 Other cases were a flat configuration, known as beta sheets. linked to the use of brain electrodes previous- Normal prion protein survives in the neu- ly used in patients with Creutzfeldt-Jakob dis- rons for only a few hours, before it is digested 292 CLEVELAND CLINIC JOURNAL Of MEDICINE VOLUME 65 • NUMBER 6 JUNE 1998 Downloaded from www.ccjm.org on October 6, 2021. For personal use only. All other uses require permission. MEDICAL GRAND ROUNDS Hü! MIM prion protein, even though both normal and mutant protein configurations have the same Known prion diseases amino acid sequence. There are two theories Diseases in animals on how this transformation might occur. In the dimerization theory, it is thought Scrapie that a mutant prion protein molecule links Bovine spongiform encephalopathy Transmissible mink encephalopathy with a normal prion protein molecule, trans- Feline spongiform encephalopathy forming the latter's helical structure into the Exotic ungulate encephalopathy beta-sheet structure. Then the two mutant molecules disassociate and move on to trans- Diseases in man form more normal prion protein molecules. Kuru In the second theory, is a single beta-sheet "Spontaneous" Creutzfeldt-Jakob disease molecule in a neuron acts as a seed to trans- "Hereditary" Creutzfeldt-Jakob disease form the normal protein molecules into a crys- Gerstmann-Sträussler-Scheinker disease Fatal familial insomnia talline aggregation of abnormal protein. "New variant" Creutzfeldt-Jakob disease In either case, the presence of the mutant, (probably human bovine spongiform encephalopathy) beta-sheet protein or prion initiates a cascade of conversion to the abnormal form. Thus, prions act like infectious agents. Prions appear to be able to cross species barri- by proteases. However, the mutant, beta-sheet ers, but often after a marked lag time. Because formation, or "prion" cannot be degraded and prions are proteins, they are unaffected by instead accumulates in the neurons. It is this sterilization techniques designed to kill most accumulation of mutant protein that is bacteria and viruses. Cooking meat, for exam- believed to cause neuron destruction and the ple, does not inactivate