The silent film clip below shows several victims of a disease called kuru. They are – or rather were – members of the South Fore, a tribe of approximately 8,000 people who inhabit the Okapa subdistrict of the Eastern Highlands Province of Papua New Guinea. In the 1950s and ’60s, a kuru epidemic swept through the South Fore, claiming the lives of more than 1,000 members of the tribe. Later it was established that the disease was transmitted by the tribe’s practice of ritualistic mortuary cannibalism.
The word kuru means “shaking death” in the Fore language, and describes the characteristic symptoms of the disease. Because it affects mainly the cerebellum, a part of the brain involved in the co-ordination of movement, the first symptoms to manifest themselves in those infected with the disease would typically be an unsteady gait and tremors. As the disease progresses, victims become unable to stand or eat, and eventually die between 6-12 months after the symptoms first appear.
Kuru belongs to a class of progressive neurodegenerative diseases called the transmissible spongiform encephalopathies (TSEs), which also includes variant Creutzfeldt-Jakob Disease (vCJD) and bovine spongiform encephalopathy (BSE, more popularly known as “Mad Cow Disease”). TSEs are fatal and infectious; in humans, they are relatively rare, and can arise sporadically, by infection, or because of genetic mutations. They are unusual in that the infectious agent which transmits the diseases is believed to a misfolded protein. (Hence, the TSEs are also referred to as the prion diseases, “prion” being a shortened form of the term “proteinaceous infectious particle”).
BSE first appeared in the U.K. in 1986. A decade later, a young man from Wiltshire who had eaten contaminated beef became the first victim of vCJD. Health officials realized that the disease was spreading among livestock because of the practice of feeding them offal. They warned that tens of thousands of people could be at risk and subsequently more than 200,000 cattle were culled in order to prevent this, at a huge expense to the British economy.
To date, though, only 156 people in the U.K., and a much smaller number in other countries, have died from vCJD. However, a longitudinal study of the Fore people, published 2 years ago, suggests that kuru and related diseases may have an incubation period of up to 50 years, leading some researchers to argue that we may yet face an epidemic of vCJD. And last month, neurologists reported a previously unidentified prion disease which has killed 10 people in the U.S. and infected 6 others.
The prion hypothesis was proposed by Stanley Prusiner in 1982. It states that TSEs are transmitted by an abnormally folded form of the prion protein. The normal form of this protein is present in all cells, but its function remains unknown. The abnormal prion protein is insoluble and prone to accumulate in clumps which give the brain tissue a characteristic sponge-like appearance (spongiform encephalopathy means “sponge-like brain disease”). The clumps cause the shaking and abnormal gait, because they make cerebellar cells unable to properly conduct nervous impulses.
It is now known that the clumps of abnormally folded prion protein can break down into smaller fragments. Thus, if infected tissue is consumed, these fragments act as “seeds“, which cause the normal protein in the host cells to adopt the abnormal configuration and begin to accumulate, in a process called a nucleation-polymerization reaction. The proposed structures of both forms of prion proteins are shown in this figure. The abnormal, pathogenic form of the prion protein (on the right) has a higher proportion of structures called beta-pleated sheets, and a lower proportion of alpha-helices, than the normal cellular form (left). The normal form of the protein is thought to be converted to the abnormal one by a series of point mutations. Recent evidence suggests that the abnormal prion protein is not itself toxic neurons, but rather that its propagation generates a toxic by-product.
Experiments in yeast have implicated heat shock proteins in the propagation of the prion seed. Heat shock proteins are a large family of molecules present in all cells and in all organisms. Their concentrations are increased in response to elevated temperatures, but they also act as “chaperones” which assist newly-synthesized proteins in assuming their correct three-dimensional structure, and prevent them from clumping together. Thus heat shock proteins are also involved in disassembling the clumps of abnormally folded prion proteins. In yeast cells with a mutated form a specific heat shock protein, the clumps of prion protein are not fragmented, and so are not passed on during cell division.
Following the outbreak of kuru among the Fore in the 1950s, cultural anthropologists quickly established that the disease was transmitted by the practice of mortuary cannibalism. When an individual died, the female relatives were responsible for dismembering the body. They would remove the brain, arms and feet, strip the muscle from the limbs and open the chest and abdomen to remove the internal organs. Those that died of kuru were highly regarded as sources of food, because they had layers of fat which resembled pork. It was primarily the Fore women who took part in this ritual. Often they would feed morsels of brain to young children and elderly relatives. Among the tribe, it was, therefore, women, children and the elderly who most often became infected.
Although the Fore’s cannibalism was outlawed by Australian authorities in the late 1950s, cases of kuru contined to appear among members of the tribe. This led John Collinge, head of UCL’s Department of Neurodegenerative Disease, to travel to Papua New Guinea to investigate. Between 1996 and 2004, Collinge and his team collected information about the life histories of Fore tribesmen and women, and during that time, they identified 11 new cases of kuru. Writing in The Lancet, Collinge concluded that “the minimum estimated incubation periods ranged from 34 to 41 years… [but] incubation periods of infection with human prions can exceed 50 years,” and last week he reiterated the possibility of a vCJD epidemic:
We must not forget that almost every person in the UK was exposed to the agent that causes variant CJD. It went through the entire food chain, not just in burgers but in cakes containing gelatins made from meat products. Even cosmetics contained beef-derived chemicals then.
It is, however, possible that some members of the Fore tribe continued to practice cannibalism after it was outlawed. This could explain the cases that emerged during Collinge’s study, but does not necessarily preclude a long incubation period for kuru. It would, however, be very difficult to determine how effectively the law against cannibalism was enforced by the Australians. It is prudent to continue research into the prion diseases, because it is possible that we may face an epidemic of vCJD. (A study published last year, also led by Collinge, showed that prion disease symptoms and pathology are reversible.)
During their time with the Fore tribe, Collinge and his colleagues collected DNA samples from 10 of the 11 new cases of kuru that had emerged. Analysis of the samples showed that the 10 individuals were all homozygous for (i.e. had two identical copies of) one particular allele, or version, of the prion gene, which may have made them susceptible to infection. Similarly, the 156 British victims of vCJD could, Collinge says, “represent a distinct genetic subpopulation with unusually short incubation periods for BSE.”
The newly identified prion disease, which has been named protease-sensitive prionopathy (PSPr), was reported by American physicians in last month’s Annals of Neurology. In the 11 cases, the average age of onset of the disease was 62, and its duration, from the appearance of symptoms to time of death, ranged from 10 months and 5 years. Unlike most human prion diseases, the loss of motor function had been accompanied by cognitive decline, and the post-mortems showed a distinctive neuropathology.
Lead author Pierluigi Gambetti, head of the National Prion Disease Pathology Surveillance Center in Ohio, believes that the disease has probably “been around for many years, unnoticed.” PSPr differs from other prion diseases in several ways. The disease gets its name because the prion protein isolated from the victims, unlike that from other prion diseases, was susceptible to degradation by enzymes called proteases. The abnormal prion protein was also detected at concentrations 16 times lower than in other prion diseases.
Gambetti insists that the disease is likely to caused by genetic and not environmental factors, and that there is no need for alarm. Significantly, none of the 10 victims had mutations in the prion gene, but several of them had close relatives who had been diagnosed with dementia. Thus, it seems that a mutation or mutations outside of the prion gene can generate prion-like pathology. This is the case in Alzheimer’s Disease, in which there are mutations outside of the gene encoding the amyloid precursor protein. The new study should lead to a better understanding of the genetics of prion diseases, and Gambetti is now carrying out experiments in mice to determine how the new disease is transmitted.
Collinge, J. et al (2006). Kuru in the 21st century: an acquired human prion disease with very long incubation periods. Lancet 367: 2068-2074. DOI: 10.1016/S0140-6736(06)68930-7
Gambetti, P. et al (2008). A novel human disease with abnormal prion protein sensitive to protease. Ann. Neurol. 63: 697-708. DOI: 10.1002/ana.21420