Prions – morphing agents of diseasePrions are the proteins that cause deadly brain diseases. But how do they cause disease and what is their normal role in the body?
Key text
Back to basics You will get more from this topic if you have mastered the basics of DNA and genes – this link will take you to an annotated list of sites with helpful background information. Key textThe discovery of prion proteins as infectious agents began in the 1980s with an outbreak of mad cow disease in the United Kingdom. Symptoms and pathology of mad cow disease Mad cow disease is a fatal condition affecting the nervous system of cattle. In an affected animal, the brain develops tiny holes. The animal loses control over its movements and its behaviour changes – so it seems mad. The tiny holes in the brain are areas where brain cells have degenerated or died. Because of all these holes, the brain of an animal with mad cow disease looks like a sponge – hence the clinical name of the disease, bovine spongiform encephalopathy (BSE). The first diagnosis was in 1986 BSE was first diagnosed in Britain in 1986. It is very similar to scrapie, a well-known disease in sheep that has been recorded for more than 200 years. Scrapie is also a spongiform encephalopathy and is always fatal. Why did mad cow disease suddenly appear? Mad cow disease started in Britain after cattle were fed meat- and bone-meal, a protein supplement made from offal from cattle and sheep. This practice had been going on for some time before BSE appeared, but in the early 1980s the way in which offal was processed changed – the high temperatures and the quantities of chemical solvents used to sterilise the material were reduced slightly. This may have allowed the disease agent, which is very resistant to all forms of sterilisation, to survive. The origin of BSE is not known: It may have been a spontaneous case of BSE arising in cattle or scrapie in sheep. The most important part of the cause, however, was the use of intraspecies recycling (or cannibalism carried out as a regular practice) in the cattle industry, which allowed repeated cycles of transmission and amplification. Kuru – a human disease with similar symptoms and a similar cause In 1957, D. Carleton Gajdusek (United States National Institutes of Health) and Vincent Zigas (Australian Public Health Service) described a strange disease among the Fore highlanders of Papua New Guinea. Victims of the condition showed a gradual loss of coordination, which progressed to complete motor incapacity and death. The course of the disease lasted 12 months on average and was always fatal. It affected all ages and both sexes, but it was most common in adult women.
Kuru began to disappear from Papua New Guinea after cannibalism was outlawed. However, it has not yet gone altogether: Remarkably, a few cases are still occurring in the early 2000s with incubation periods of up to 50 years. Creutzfeldt-Jakob disease – another spongiform encephalopathy Creutzfeldt-Jakob disease (CJD) is another spongiform encephalopathy that occurs in humans. It is very rare: Only about one person in a million per year is affected. Because CJD resembles kuru pathologically, Gajdusek and his colleagues tested it in chimpanzees and found that it too was transmissible. Subsequently it was discovered that when material from a CJD sufferer is transferred to another person, then that person is likely to develop the disease. Possible sources of person-to-person transmission include growth hormone and blood transfusions (Box 1: Public health issues). But the story of contaminated human health products doesn't explain every case of CJD. The majority of cases seem to occur spontaneously, and the disease is more likely to strike in older people. About 10 to 15 per cent of cases are inherited as a result of a mutation in the DNA, which means it runs in families. What causes spongiform encephalopathies? For many years no-one knew exactly what was causing the spongiform encephalopathies. A virus was presumed to be the culprit, even though biologists couldn't find anything that looked like a virus in sick animals. The agent was called a slow (or unconventional) virus because of the long incubation period between inoculation and disease – two years for kuru in chimpanzees – and the long clinical course before the inevitable fatal outcome. In the 1970s experiments were starting to show that the mystery microbe in sheep (the scrapie agent) was remarkably resistant to many forms of sterilisation. Healthy animals could be infected even after the extract from diseased animals had been zapped with radiation or treated to destroy the genes of any bacterium or virus. It was this ability to survive normal sterilisation that enabled BSE to be passed on to cattle by meat-and-bone meal. The microbe that causes scrapie seems to have no genes By 1982 an American scientist, Stanley Prusiner, following the work of the radiation biologists, had concluded that the scrapie agent seemed to have no nucleic acid, the material of which genes are made. Clearly, then, it was not a virus or any other known organism and was almost certainly not alive in any real sense. But it appeared to be able to multiply. A new class of infectious agents – prions When Prusiner discovered that he could make extracts of infectious scrapie that seemed to be pure protein, he concluded that the scrapie agent was definitely composed only of some sort of protein and coined the word prion to describe it. He later found that the scrapie prion consisted of just one protein chain, folded in an abnormal way that made it remarkably strong and resistant to digestion.
The scientific establishment was sceptical A protein-only infectious agent was a revolutionary idea because of what was known about living organisms. All known organisms, however small and simple, have both protein and nucleic acid. One cannot exist without the other in a living system. A protein doesn't just appear: Something must be making it, so it must have access to a nucleic acid that carries the information for its construction. Prion genes are in the host DNA Recent research shows that instructions for making prion protein are on a gene that all mammals have and is mainly active in nerve cells. This gene normally produces a protein that causes no harm. But a slight change in the gene, or in the environment in the cell where the protein assumes its final shape, and the protein produced may flip into a different shape, converting it to a prion. So prions can be produced by a chance alteration in their shape (which explains the origin of sporadic CJD), a genetic change (which explains familial CJD) or when a normal prion protein comes in contact with a prion (which explains transmission through the consumption or injection of infected brain material). As far as we can tell, these abnormal proteins are useless proteins. They are not fully broken down and accumulate in the brain as an insoluble complex of proteins called an amyloid. Nor do we know what, if anything, normal prion proteins do, except that they are found in the outer membrane of neurones, the nerve cells of the brain. In ways not yet understood, the interaction of prions with the normal cellular prion proteins damages the cell and leads to its slow degeneration and death. This releases prions, which can then induce more prions on the surface of surrounding cells, causing more degeneration and death of cells. This process of spreading cell death accounts for the holes in the brain. The current idea is that other tissues are not much affected because prion protein is mainly produced in nerve cells. Lymphoid cells also have a lot of prion protein and they are important in spreading the infection to nerve cells. However, lymphoid cells are readily replaced, whereas a process that destroys neurones, even a slowly progressive one, will lead to disease, since nerve cells cannot normally be replaced. Transmission of animal spongiform encephalopathies to humans All spongiform encephalopathies, including CJD, are caused by prions. A new variant form of CJD (vCJD), first described in 1996, is the human form of mad cow disease: This was transmitted by eating infected beef products. Since prions exist mainly in nervous tissue, you would need to eat nervous tissue to become infected; so why was there such a worry about beef, which is simply muscle tissue?
Similarity in prions is required for transmission between species Theory suggests that prions from one mammal cannot readily infect another mammal species, unless the normal prion proteins of the two species are quite similar in their shape. If not, they can't be altered by contact with the prion of the other species. However, this whole theory is based on probability, and even an event with very low probability can occasionally occur. Moreover, this probability is hard to predict from genetics. For example, it was assumed that because sheep scrapie does not transmit to humans, neither would BSE. Unfortunately, this assumption proved to be wrong. What is the situation in Australia? Australia is currently free of scrapie and BSE. Since 1988 the Australian Quarantine Inspection Service has prohibited the importation of live animals and bovine products from the United Kingdom and from any other country that is not BSE-free, in an attempt to keep these diseases out of Australia (Box 2: The Australian Quarantine Inspection Service and the need for quarantine). Researchers in Australia are working on different aspects of prion proteins and CJD (Box 3: Australian researchers looking at prion proteins and CJD). Though the individual risk of getting human BSE is low, the consequences of doing so are devastating. With as yet no blood test, no cure, and no certain means of decontamination, prions and prion diseases raise many complex practical, public health and ethical issues. Boxes 2. The Australian Quarantine Inspection Service and the need for quarantine 3. Australian researchers looking at prion proteins and CJD Related Nova topics: Getting our heads around the brain Box 1. Public health issuesBecause human BSE is a human prion disease, not a bovine one (by the strange nature of prion transmission), the probability of transmission from person to person is high. There is therefore considerable concern world-wide about the large number of people who may unwittingly be incubating vCJD. Even though they may die of some other cause, during life they represent a risk of secondary transmission of vCJD through blood or contamination of surgical instruments. Why is there concern about blood transfusions? Most spongiform encephalopathies, including CJD in its sporadic and familial forms, are confined to the central nervous system. However, one additional complication of human BSE or vCJD is that the infectious prion is present also in lymphoid tissue such as tonsils and the white cells of the blood. Furthermore, it is present there during the incubation period of the disease, which in some cases can be very long. Already there have been three probable transmissions of vCJD in the UK from blood transfusions given some years before the blood donor came down with variant CJD. Anyone who lived in the UK from 1980 to 1996 is potentially at risk of getting vCJD (human BSE). Such people, as well as those who have had a blood transfusion in the UK, are not acceptable as blood donors. Human growth hormone injections and CJD People whose bodies weren't making enough growth hormone were given injections of hormone extracted from the brains of corpses. Tragically, some of the people receiving the hormone developed CJD. It was found that the hormone they received had come from people infected with CJD. Nowadays, human growth hormone is safe to use because it is made using genetic engineering techniques, rather than being extracted from human brains. Related sites
Box 2. The Australian Quarantine Inspection Service and the need for quarantineAustralia is the most isolated of all the populated continents. This isolation has meant that Australia is free of many of the undesirable pests and diseases that occur in other areas of the world. The job of the Australian Quarantine and Inspection Service (AQIS) is to prevent the entry of these pests and diseases. The word 'quarantine' comes from the Italian word quaranta, meaning forty. This refers to the fact that a detention period of 40 days was imposed on ships arriving from areas where cholera, yellow fever or bubonic plague occurred. Modern quarantine still operates on similar principles by holding imported animals and plants for observation, during which time any diseases carried by them should become apparent. In addition AQIS identifies those substances or organisms that, if imported, would be likely to cause an outbreak of disease, and it polices bans on their importation. Most people have heard of rabies and foot-and-mouth disease, and are aware that these animal diseases should be kept out of Australia. But there are also many devastating plant diseases and pests that also need to be kept out. The plant quarantine section of AQIS identifies the viral, bacterial and fungal diseases likely to threaten Australian agriculture. AQIS also attempts to prevent the entry of plant parasitic insects and nematodes, many of which spread plant diseases. Of equal importance is the exclusion of foreign plant species that may enter as seeds or weeds in the soil around imported plants. The devastating effects of exotic plants such as prickly pear, lantana or privet on agricultural land and native bushland are well known. The inspectors and research scientists working in quarantine have the unenviable task of balancing the often competing interests of tourism, agriculture, politics and business to provide an efficient service without compromising the safety of the environment and agriculture. The enormous increase in the number of international air travellers over the past 30 years has brought with it the problem of inspecting baggage, aeroplanes and containers for quarantinable items. Agriculture demands access to new breeds or varieties of animals and plants developed overseas, and these must be introduced into Australia without introducing associated pests and diseases. The amount of time that the introduced organisms spend in quarantine must be minimised to reduce the temptation to import them illegally. The World Trade Organisation aims to prevent countries using quarantine conditions as a barrier to trade. Quarantine bans or limitations must therefore be made on sound scientific grounds to be justifiable to our trading partners. Finally, quarantine officers must keep up with new discoveries and technological advances and be aware of exotic organisms that may devastate our native flora. Related sites
Dr Jill Gready is a Senior Fellow in the John Curtin School of Medical Research at the Australian National University, Canberra, and Leader of the Computational Molecular Biology and Drug Design Group. One current project of this group is to predict the structure of the prion protein implicated in CJD. Dr Gready is looking at the normal and abnormal forms of the CJD prion protein. The work of Gready's group is primarily computer-based, using databases and molecular models to work out the structure of the prion protein. Specific questions that could be answered as a result of this project are:
Dr Simon Hawke of the Brain and Mind Research Institute at the University of Sydney is looking at the response of the immune system to prions, and is developing methods for early diagnosis and immunotherapy treatments. Related sites
Teachers notes
Teachers notes
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Teachers notes
Teachers notes Prions seem to resist the action of proteases and heat treatment (at comparatively low temperatures) because of the way in which the protein chain is folded. The normal prion protein is folded into four alpha-helices whereas the infective form of the protein folds into beta-sheets. Even if they are not broken down by cooking or digestion, ingested prions would still need to be able to move from the digestive tract to the spinal cord and brain where they are found in the greatest number. Intact prions (not broken down into their constituent amino acids) seem to be able to pass across the gut wall by a form of pinocytosis or perhaps through lesions directly into the blood stream. One suggestion of how it gets to the brain is via the lymphatic system to the spleen and then via spleen nerves to the spinal cord and brain.
Teachers notes
Teachers notes No live animals, embryos or semen can be imported from the United Kingdom. This restriction has been in place since 1988. Regulations about importing animals from other countries vary depending on the country. General information about Australia's quarantine measures can be found in Box 1.
Teachers notes Debates are only effective if the participants are well informed on the topic. Encourage students to prepare for a debate by having each student produce a summary of appropriate facts, or by dividing the class and having half prepare arguments for one side of the topic and half prepare arguments for the other side. Students could do this preparation individually or in groups. Alternatively, the debate could be preceded by a discussion of the topic, followed by an opportunity for students to collect information highlighted by the discussion.
Australasian Science July 2004, pages 32-33 Evolutionary clues to prion diseases (by Marko Premzl, Jennifer Graves and Jill Gready) Describes computer analysis of gene sequences that suggests a possible role for prions.
Nature 12 January 2006, pages 134-135 Prion disease: The shape of things to come (by Roxanne Khamsi) Assesses the risks of making large amounts of new prion proteins to study transmissible spongiform encephalopathies.
Nature Reviews Microbiology 1 March 2006, pages 201-211 Prions and their lethal journey to the brain (by Neil Mabbott and G. Gordon MacPherson) This technical paper reviews the current understanding of how prions make their way to the brain.
New Scientist 13 September 2008, page 14 Is rare form of BSE already in people? (by Andy Coghlan) Reports on a new form of mad cow disease.
12 July 2008, page 13 Ten people felled by new CJD-like disease (by Andy Coghlan) Describes a new CJD-like disease caused by prions.
19 January 2008, page 12 Super-sensitive BSE tests may not make meat safer (by Debora Mackenzie) Discusses the need for more sensitive BSE tests.
25 October 2007, page 10 Absent prions blow hole in BSE theory (by Andy Coghlan) Reports on findings which suggest abnormal prion proteins might not cause BSE-like diseases.
26 August 2007, page 18 ‘Shadoo’ prion sheds light on BSE Reports on the identification of other types of prions in the brain.
7 July 2007, page 14 Prions prevent the progress of Alzheimer’s (by Andy Coghlan) Reveals the link between prions and Alzheimer’s disease.
17 March 2007, page 11 New twist in tale of BSE’s beginnings (by Debora Mackenzie) Suggests that BSE may have originated in cattle rather than sheep.
16 December 2006, page 7 Blood risk of vCJD highlighted Reports that the blood from healthy donors may transmit prions that cause vCJD.
27 May 2006, page 18 Double rethink on prion diseases (by Andy Coghlan) Suggests that some prion diseases can be transmitted when animals lick each other.
15 April 2006, page 18 Are prions the real cause of BSE and vCJD? (by Andy Coghlan) Suggests that abnormal prions may not be the only infectious agent of prion diseases.
18 March 2006 How mad cows have been struck off the world’s menu (by Andy Coghlan) Says that bans on the export of meat products and feeding cattle meat- and bone-meal limited a major outbreak of disease.
18 February 2006, page 12 When prions are 'good for the brain' (by Stu Hutson) Describes a potential role for normal prions in controlling development of neurones.
29 October 2005, page 19 Did prior infection save British from vCJD? Reports that infection with a mild strain of prion may protect against later infection by more severe forms.
23 July 2005, pages 33-36 Red alert: The war on tainted donated blood (by Sylvia Pagán Westphal and Clare Wilson) Covers the efforts to keep donated blood safe for transfusions.
13 June 2005 US 'rediscovers' its second mad cow Describes possible errors in the reporting of BSE in the USA.
26 March 2005 Prion antibodies open way for vCJD vaccine Reveals that antibodies can be made against prions in mice.
4 February 2005 First human case of mad cow disease in Japan (by Debora MacKenzie) Describes the first case of vCJD to be reported in Japan.
12 January 2005 Canada discovers its third mad cow (by Debora MacKenzie) Discusses the third case of BSE in Canada.
7 August 2004, pages 32-41 This special report on BSE contains the following articles:
17 July 2004, pages 30-33 The shapeshifters (by Sylvia Pagán Westphal) Suggests that the normal role of prions and prion-like proteins is to act as biological clocks.
28 November 2002 BSE may cause more CJD cases than thought (by Emma Young) Suggests that the increase in cases of sporadic CJD may be due to the BSE epidemic.
Scientific American January 2008, page 34 Progress against prions (by Gary Stix) Reports on the development of treatments for the human form of mad cow disease.
July 2004, pages 60-67 Detecting mad cow disease (by Stanley B. Prusiner) Prusiner, the winner of the 1997 Nobel prize for his discovery of prions, describes several tests used by researchers for rapidly identifying the presence of the disease-causing form of the BSE prion.
Mad cow disease: The BSE epidemic in Great Britain (Access Excellence, USA) An interview with Dr Frederick Murphy which provides a good overview of the BSE epidemic in Great Britain. Includes an explanation of prions, current research priorities and possible future treatments for prion-related encephalopathies.
Australian Government Department of Health and Ageing
BSE and imported beef products (Food Standards Australia and New Zealand) Provides answers to questions about BSE.
The emerging European epidemic of variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy: Lessons for Australia (Medical Journal of Australia, 2001) According to Professor Colin Masters, Australia needs to ensure that precautions to minimise the risk of BSE are implemented and communicated to the public.
Cannibals (Catalyst, 4 September 2003, Australian Broadcasting Corporation)
An interview with Professor Michael Alpers about research suggesting that the practice of cannabalism was more widespread that previously thought.
Prions: Puzzling infectious proteins (National Institutes of Health, USA) Shows four levels of protein structure to explain how prions cause disease. Also describes the human diseases linked to prions.
About human prion diseases (National Prion Disease Surveillance Center, USA) Describes sporadic, familial, iatrogenic, vCJD and kuru forms of prion diseases.
World Health Organisation
gene. The basic unit of inheritance. A gene is a segment of DNA that specifies the structure of a protein or an RNA molecule. genetic engineering. A set of procedures whereby a specific piece of DNA can be excised from a chromosome and inserted into the DNA of a chromosome of a different organism. hormone. A substance produced in one part of the body and carried by the blood to another part of the body where it causes a response (eg, insulin, produced by the pancreas, that promotes the uptake of glucose by body cells). For more information see The hormones of the human (Kimball's Biology Pages, USA) and The hormones (Center for Bioenvironmental Research, Tulane and Xavier Universities, USA). normal prion protein. Special proteins that can change shape and be stable in the new form. Most proteins fold into a particular shape that allows them to perform their function, and if they don't fold into the correct shape they get degraded and the body gets rid of them. prion. A small proteinaceous infectious particle which resists inactivation by procedures that modify nucleic acid. Most researchers think that prions are the cause of several diseases including scrapie in sheep, bovine spongiform encephalopathy in cattle and kuru and Creutzfeldt-Jakob disease in humans. More information about prions can be found at Prions: Puzzling infectious proteins (National Institutes of Health, USA). protein. A large molecule composed of a linear sequence of amino acids. This linear sequence is a protein's primary structure. Short sequences within the protein molecule can interact to form regular folds (eg, alpha helix and beta pleated sheet) called the secondary structure. Further folding from interaction between sites in the secondary structure forms the tertiary structure of the protein. Proteins are essential to the structure and function of cells. They account for more than 50 per cent of the dry weight of most cells, and are involved in most cell processes. Examples of proteins include enzymes, collagen in tendons and ligaments and some hormones. More information can be found at Protein structure and diversity (Molecular Biology Notebook, Rothamsted Research, UK). vesicle. A small sac surrounded by a membrane within the protoplasm of a cell.
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