BSE and vCJD: Their biology and management
BSE and vCJD: Their biology and management

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BSE and vCJD: Their biology and management

6 Is prion-like behaviour exceptional or the norm?

At the time of writing (2005), it is widely - but certainly not universally - accepted that TSEs are triggered by prions. Prions consist entirely and exclusively of PrP protein. In particular, they contain no nucleic acid - and hence no genetic information - at all. An animal may either produce its own disease-triggering PrPSc protein (in the case of inherited and probably some sporadic TSEs) or PrPSc protein from elsewhere might start a 'chain reaction' in which PrPC protein synthesised by the animal may be converted into the PrPSc conformation. Three main objections to this protein-only explanation of TSEs have been put forward.

The first objection was that prion biology somehow contravenes Francis Crick's 'central dogma' of biology: DNA makes RNA makes protein (which, in turn, produces the organism's phenotype).

Question 42

Do prions contravene the 'central dogma'?

Answer

No. Every PrP molecule - whether PrPC or PrPSc - is coded for by a PrP gene. The amino acid sequence of the PrP molecule is specified by the sequence of nucleotides in the gene and is not altered by any change of conformation that the molecule may later undergo. (However, implicit in the central dogma is that the same protein produces the same phenotype; in the case of PrP, this is not the case.)

While this first objection can readily be dismissed as the sort of misunderstanding that tends to arise as people come to terms with new concepts in biology or any other science, the other two objections must be taken more seriously.

The second objection is that it is extremely difficult to demonstrate that TSEs are caused by purified prion protein with absolutely no involvement of another molecule (which might contain genetic information) so small that it is as yet undetectable.

The third objection relates to the existence of different strains of particular TSEs. For instance, there are at least 20 distinct prion strains in mice and several strains of scrapie in sheep. The existence of these different strains might be explained by there being different alleles of the PrP gene within a species. However, the perpetuation of these distinct strains through successive cycles of injecting infective prions into members of the same species (e.g. mice) and, particularly, into members of a different species (e.g. mice TSE transmitted to hamsters) cannot be explained in this way.

Question 43

Suppose a TSE strain in mice was due to a particular allele of the PrP gene that codes for a particular sequence of amino acids in the resulting PrP protein. Explain why the perpetuation of this TSE strain through a series of mice possessing different alleles of the PrP gene and (especially) through a series of animals of a different species (such as hamster), following initial injection of PrPSc from the first mouse, would be surprising.

Answer

The PrPSc injected initially would have the amino acid sequence of the first mouse. Any new PrPSc produced in the second mouse as a result of interaction with this injected PrPSc would have the amino acid sequence of the second mouse and not that of the first. In other words, the original strain of TSE would be lost as the TSE passed through the second mouse or any subsequent ones. Similarly, one would expect a hamster infected with a particular strain of mouse TSE to develop hamster TSE and not a particular strain of mouse TSE. One certainly wouldn't expect to be able to inject PrPSc from the first hamster into a second hamster and for this second hamster to develop the original strain of mouse TSE.

It is clear therefore that the existence of different prion and TSE strains cannot be explained by invoking different sequences of amino acids in PrP proteins.

Question 44

If different TSE strains cannot be explained by differences in the genotypes of the host animals, what is the only remaining logical explanation other than prions containing at least small amounts of nucleic acid? (Hint: Think in terms of molecular conformation.)

Answer

If the existence of several different TSE strains cannot be explained by genetics, then it can only be that PrP proteins with the same sequence of amino acids can fold into several different conformations. In other words, there is more than one way in which the conformation of PrPSc differs from that of PrPC. Furthermore, each PrPSc conformation perpetuates itself by causing any PrPC molecule with which it interacts to adopt its own particular conformation, even if the PrPC molecule has a slightly different amino acid sequence than its own.

Confirmation that absolutely purified prion protein is infective and that prion strains are a consequence of distinct, self-propagating conformations of otherwise identical amino acid chains came in 2004 from experimental work on the fungus Saccharomyces cerevisiae. Perhaps surprisingly, prions are found in several species of fungi. However, these prions are not disease-causing and may even be beneficial to the host. The protein with prion properties used in this work, called Sup35p, is concerned with terminating the synthesis at ribosomes of amino acid chains.

That the ability of several proteins to adopt different conformations may benefit their fungal hosts - and certainly not harm them - suggests that we should not necessarily regard prions exclusively as disease-causing 'rogue' molecules. Indeed, as more research is done on prion biology, it is becoming clear that the ability to acquire and transmit change in conformation may even be part of 'normal' biology. Two diverse research fields in which prion-like behaviour in proteins is implicated are cellular time-keeping and memory.

James Morré of Purdue University in West Lafayette, Indiana, has shown that proteins called ECTO-NOX (found in both animals and plants) can oscillate in unison between two conformations and that this might be the basis of timekeeping in cells. It may therefore be no coincidence that mice engineered to lack prion protein have problems maintaining daily (or circadian) rhythms.

Nobel Laureate Eric Kandel of Columbia University in New York has suggested that prion-like proteins might be responsible for 'marking' neurons prior to the laying down of more connections (or synapses) between them. Such 'marking' is believed to be the basis of memory. This suggestion was based on Kandel's own work on the sea slug Aplysia (whose CPEB gene is very similar to the mammalian PrP gene).

There is now little doubt that TSEs are caused by the build-up of PrPSc proteins in brain cells and that this build-up usually results from a 'chain reaction' in which contact between PrPC protein and PrPSc protein causes the former to be converted into the latter. Scientific research into prions is also beginning to reveal that other proteins engage in similar conformation-changing behaviour and that this may be an aspect of 'normal' biology that has remained unsuspected until quite recently. Interesting developments in this field are likely to occur during the lifetime of this course.

Activity 4

Timing: 0 hours 15 minutes

Compare your own notes on the relevance of material in Sections 3, 4, 5 and 6 to the theme of ethical issues with the explanations given below. Note that, for the remainder of this course, the first letter of all four themes will be highlighted in bold.

Discussion

Since cattle are herbivorous, some people would object to them being fed tissues derived from other animals (Section 3) because it challenges their normal behaviour. Indeed, most people were probably unaware of this practice until BSE started to be discussed. Examples of experimental procedures that some people would consider ethically unacceptable include the injecting of brain tissue from an infected animal into the brain of another in order to investigate the incubation period of TSEs in relation to lifespans (Section 3) and injecting infective prions through a succession of species to investigate perpetuation of strains (see above). The issue of cannibalism and whether it should be regarded as taboo or a mark of respect for the dead comes up again (Section 4).

A very important ethical issue is whether or not information that someone was incubating vCJD should be provided to them or withheld (Section 5). At present, it is not possible to cure people of vCJD and there is only very limited evidence that progress of the disease can even be slowed in those already displaying its symptoms. Given the profound psychological damage this knowledge might cause, the distinct possibility that the person might in any case die from an unrelated cause before developing vCJD and the fact that precautions have been put in place to minimise their infecting someone else in the meantime, there is a real challenge in deciding whether to pass on this information. Of course, the ethical balance could change dramatically if a treatment became available that could prevent the development of vCJD but only if it were given before the appearance of symptoms.

A further consideration would be the cost of any treatment and whether it should be available to all or only to those who could afford it. Indeed, a very important issue is how much resource - that could be used for other purposes, medical or otherwise - should be devoted to trying to develop either a preventative treatment or a cure for a disease such as vCJD. And who should foot the bill? As noted in the text (Section 5), this does rather depend on the eventual total number of people likely to develop the disease.

Having covered the molecular biology and epidemiology of BSE and vCJD, we can now examine how the BSE/vCJD episode was managed.

S250_4

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