Review of rogue prion protein

Molecular Evolution of Prions

chart showing prion evolutionary tree commentary by Henry Gee ... 9 May 1996 Nature

The disturbing link between the prions that cause Bovine Spongiform Encephalopathy (BSE) in cattle and Creutzfeld-Jakob disease (CJD) in humans comes from a study of the evolutionary relationships of prions in a wide variety of mammals. The normal prion found in cattle shares two biochemical features with the prion found in humans and apes. Crucially, neither of these features are found in the prion of sheep -- the prion which, when mutated, causes the disease called 'scrapie'. These biochemical features -- changes in the amino-acid sequence of the prion protein -- occur in a part of the protein thought to be involved in the onset of prion-mediated diseases such as CJD and BSE.

The discovery is a shattering blow for the evolutionary argument that because humans seem unable to contract prion diseases from sheep infected with scrapie, they would be unlikely to contract CJD from contaminated beef. The study, published in the 25 April issue ofNature comes from a team of researchers based in Oxford, in the UK, including Professor T. R. E. Southwood, a former advisor to the British Government on BSE.

Prions are proteins that occur in the brains of all mammals so far studied. The normal function of prion proteins is not understood, but recent research on mice that lack the PrP gene -- which encodes the prion protein -- suggest that it protects the brain against dementia and other degenerative problems associated with old age. Sometimes, 'rogue' prions are produced by genetic mutations. This explains why some cases of CJD in humans are inherited.

Another inherited human prion disease is so-called Fatal Familial Insomnia. There is some evidence that this results from a deficiency of the normal prion protein, a deficiency that occurs because mutant prions are unable to fulfil their normal functions.

In addition to causing disease through inherited genetic mutations, mutant prions are capable of turning into 'rogue' disease agents. Transmitted from an infected animal or human to a new host, they convert any 'normal' prions they encounter into copies of themselves. This conversion process eventually results in spongiform encephalopathies such as BSE and CJD.

The transmission of disease depends on the rogue prion being similar enough to the host prion to be able to 'lock in' to its structure and convert it. Transmission works best between animals of the same species. For example, a prion disease called 'kuru', found in the Fore tribe of New Guinea, is spread by ritual cannibalism, in which mourners eat the brains of their dead relatives. This practice has since ceased. But there is some evidence that rogue prions can jump the barrier between species, provided that the prions of donor and host are similar enough for the conversion process to occur.

Cattle and sheep are extremely close evolutionary relatives. They belong to the family Bovidae, and share a common ancestor that lived probably no more than 20 million years ago. So it is no surprise -- in hindsight -- that cattle could contract a prion disease when fed with offal from sheep contaminated with scrapie, a spongiform encephalopathy endemic to sheep. That hundreds of thousands of cattle have been slaughtered since the initial contamination shows just how easy it is for prion proteins to be transmitted from sheep to cattle.

But human beings are extremely distant relatives of bovids such as cattle and sheep. Our most recent common ancestor was alive around 70 million years ago, when mammals all looked like rats, and dinosaurs still ruled the Earth. Because of this evolutionary separation, human prions are unlikely to be similar to those of either sheep or cattle. This distance seems to be borne out by experience -- sheep have had scrapie for more than 200 years, and yet there is no known association between scrapie in sheep and CJD in humans. Given these arguments, there seems no compelling reason why humans should contract CJD from beef, either.

The evolutionary 'family tree' (above) seems, at first glance, to support this view. Prions from cattle (Bos taurus) and sheep (Ovis aries) are similar to each other, and to prions from other ungulates such as goats (Capra hircus) and deer (Odocoileus hemionus). They are quite different from those found humans (Homo), gorillas (Gorilla), chimpanzees (Pan) and a wide range of monkeys.

But this family tree was based on general features of the prions -- an overall consensus of similarity. It does not account for the significance of any particular detailed similarity or difference. Therein lies the interest of the similarities between human (and ape) prions and the prion of cattle -- similarities which occur nowhere else in the family tree, and significantly, not in sheep.

That the chance of these two similarities being shared by cattle and humans is extremely remote, should give scientists and politicians pause for thought. That these two unlikely similarities happen to occur in a part of the prion thought to be connected with disease transmission -- presumably, the conversion of normal prions into rogues -- can only be interpreted as worrying.

11 April Nature.

Rogue Prion Protein

Research into BSE and its human equivalent Creutzfeldt-Jakob disease (CJD) continues apace as Britain and Europe struggle to save their embattled beef industry. The latest insight into these diseases may even have repercussions for understanding other brain-wasting diseases, such as Alzheimer's and Parkinson's disease.

Spongiform encephalopathies are spread by a rogue form of a protein called a 'prion'. The normal form of the protein is produced naturally in the brains of all mammals, and is harmless -- but altered forms adopt the role of an infectious agent. Like a rotten apple, once inside the brain, the mutant form of prion protein turns the native protein into more copies of the deviant, infectious form. The end result is a characteristic loss of motor coordination, dementia and death, and a brain full of holes, like a sponge. Nobody understands the connection between prions and the particular pattern of symptoms that seem to be associated with them, nor why the brains of infected people or animals become spongy.

As all mammals produce prion protein, it would seem likely that it serves some useful purpose but, to everyone's surprise, mice without the prion-producing gene seem to grow up normally into healthy adult mice. Only after seventy weeks (which is late middle-age for a mouse) do things start to go wrong, according to Dr Suehiro Sakaguchi and his colleagues from the Nagasaki University School of Medicine in Japan, who report their findings in the April 11, 1996 Nature.

The prion-free mice were resistant to scrapie, the sheep equivalent of BSE. Just as a single rotten apple can do no harm in an empty barrel, a brain without prion protein cannot be taken over by the rogue form. But no-one could guess why these mice should live for so long without feeling the deficiency of the normal prion protein. Now, Dr Sakaguchi and his colleagues believe they have an explanation. The researchers noticed that their seventy-week-old prion-free mice were not as healthy as they first seemed. They developed an odd, uncoordinated gait. Their back legs began to tremble as they tried to walk, they took short tentative steps and were unable to keep a straight path. As they got older, their coordination became progressively worse, and they frequently collapsed. By ninety weeks, the mice had deteriorated even further. Hardly able to stand, most had developed spasmodic arching of their backs.

These crippling symptoms are similar to those of BSE and CJD, leading the researchers to suppose that the loss of the natural form of prion protein is to blame -- and may be the cause of at least some cases of these diseases, even in the absence of an infectious agent. There are two main ways in which the progressive take-over of the brain by the rogue prion might cause disease -- either the rogue prion itself causes damage, or the loss of normal prion means its usual beneficial function is not felt. Given the effect on these mice, it seems that we produce prion to avoid the wasting away of our brains that would otherwise come about.

Closer examination of the brains of the afflicted mice gives a good indication of what prion protein would normally be doing when there is plenty of it in the brain. The cerebellum, the part of the brain responsible for movement and coordination, had shrunk by almost one-third in the specially bred, prion-free mice.

One particular type of brain cell was particularly notable by its absence -- the Purkinje cells. Young mice, which had not yet succumbed to illness, had healthy numbers of these cells, so Dr Sakaguchi and his colleagues venture that prion prevents these cells from dying. After all, old people, whose brain cells are gradually dying off, also become progressively less coordinated in their movements. And loss of coordination is typical of many brain-wasting diseases, including Alzheimer's and Parkinson's diseases. These Purkinje cells, it seems, can survive for a while without any help, but they will soon die without the support of prion. Even with it they will eventually die, but prion certainly prolongs that inevitable moment.

This latest research may also shed some light on the inherited form of CJD, a persistent (though rare) disease. The recent frenzy in Europe came only after the reporting of several cases of a new form of CJD. The latest victims are young people, with apparently no family history of the disease, raising fears that the disease had been caught by eating beef infected with BSE. But the inherited form of CJD has long been known, affecting about one in every million people each year. One possibility might be that those susceptible to the disease have a faulty prion gene, so that they either do not produce enough prion, or produce it in a less effective form.

But Dr Sakaguchi is cautious. His mice were not the first to be bred as prion-free, and those first mice were still healthy at 93 weeks of age. Slightly different breeding techniques may account for these differences, but until further analysis is brought to bear on prion-free mice, researchers cannot be confident in their understanding of the prion protein. Whatever the outcome, it will be too late to have any effect on the current economic crisis gripping Europe.