This write-up is an attempt to give an overview of the current status of the intriguing
puzzle of
prion research. Some things are known more or less for sure, more is
suspected and
speculated, and I’ll end with some remaining
questions. The aspects per section are mentioned in pretty much of a random order.
What they think they know
1. A prion is a proteinaceous infectious particle and can induce
spongiform encephalopathies in a lot of animals, not only sheep (
scrapie),
cows (
BSE) and
humans (
CJD and
Kuru), but also rodents, minks (
TME), elks (
CWD) and probably pigs, chicken and some farmed fish.
2. BSE was first recognized in 1986, whereas
Kuru had already been identified in 1957 (not the disease-causing agent itself, but
a source where it’s residing in the
harmful conformation. More about that below), scrapie is known for at least 200 years.
3. The
harmless variant of the prion is called
PrPc (
Prion
Particle cellular), the
harmful one
PrPsc (from scrapie).
4. There are no
chemical differences found between the two variants. However, a difference in
enzyme susceptibility has been found:
plasminogen is the first
endogenous factor discriminating between the normal and
pathological prions. On the
nerve cells, the
molecules that help turn plasminogen into
plasmin are localized on the same specialized patches of
membrane as normal PrP. Now, isn’t that convenient? (FYI: plasminogen is a
pro-protease that has a function related to neuronal
exitotoxicity, it is the
inactive form of plasmin (and plasmin is thought to allows
synapses to remodel themselves, a crucial process for thought and
memory). See also points II and A.). Further, there’s this
kinetic difficult accessible but
thermodynamic stable PrPsc resulting from PrPc (see write-up
Halcyon&on).
5. There are two ways to get the prion disease:
- Inheritable: about 10-15% of the CJD cases because one (or a few) out of the 750 codons is different as a result of a point mutation in the DNA: Leucine is substituted for Proline. They’ve found 18 of those mutations up till now. Another important codon appears to be nr 129, building in Methionine into the PrP-chain instead of Valine. About 37% is so-called homozygote for this codon 129, meaning that both helices need to have this defect (“MM”). At first they thought homozygosity was required for developing the disease, but recent results show that heterozygotes will die too, the only difference is the longer incubation period. 51% of the population is heterozygote (MV, one strand coding for the Methionine and one for Valine).
Reduced PrPc-gene expression delays the onset of the disease, whereas absence of the PrP gene makes the tested knockout mice fully resistant to infection. So production of PrPc is required for the PrPc to turn into PrPsc. On the other hand, excessive PrP production results in destruction of muscles and peripheral nerves.
- Communicable: iatrogenic (e.g. via corneal transplantation, human growth hormone medicines), animal feed, food, and in some species like sheep also via blood.
6. The
infections affect different
species in different ways. The result can be no
symptoms, but being able to pass on the prions to other animals who in turn get sick (might be the case with pigs and chicken, not tested yet). When sheep eat BSE-
contaminated feed, they develop a disease
clinically similar to scrapie. But when their meat is fed to mice, the mice develop BSE symptoms. Further, BSE tends to affect the
brain and
neurons primarily, whereas the PrPsc in sheep can be found all over the body.
What they suspect
I. Some prions cause disease quickly, while other prions (in the same species) have a longer
incubation period. There is a tendency to believe that this may be dependent on the
amino acid sequence: with one or a few other amino acids built in into the chain, one (or some) crucial parts of the prion may, or may not, be less stable hence more
susceptible to changing the á-helix into the ß-sheet (i.e. PrPc into the harmful PrPsc). Tests were conducted with a PrP
hybrid built of mice PrP-gene code and flanking human PrP code, built into and expressed in mice. A hybrid protein was produced. Then brain
tissue of patients who died of CJD was introduced into the mice. Weird stuff was, that the
transgenic mice became ill much more frequently and faster than did mice carrying a full human PrP gene (diverges from mice PrP at 28 position). This suggest that similarity in the supposed
active region is important, as well as a “
chaperone”
molecule normally involved in folding
nascent protein chains, recognized one or both mouse-derived regions of the PrPc.
II. PrPc is predominantly found on the surface of neurons, attached by a
glycoinositol phospholipid anchor. What is its purpose there? (See also 4)
III. Ingested prions may be absorbed across the
gut wall at
Peyers patches. The resident
bacteria may be facilitating a protective
immune response (but others note that the
white blood cells don’t respond to prions at all). The
lymphoid cells take up the prions by
phagocytose, so that the prions can travel to
lymphoid nodes,
spleen and
tonsils and probably replicate there. “Eventually they gain access to a nerve” (How?) and can propagate or travel via the
axon and
spinal cord up to the brain. Either
glial cells or neural cells can propagate the disease independently. And the fact that
intercerebral injection of PrPsc alone doesn’t cause
pathology means that “cells must be making PrP for a pathological result”. I don’t think that’s a good conclusion, instead of “must” it should be at least “may” (and see point II of this section): the fact that there’s no known
physiological function doesn’t mean that it doesn’t exist. If you don’t know where, what and how exactly to test (as is the situation trying to solve the mystery around prions; “standard” infectious particles are normally
micro-organisms or
viruses, at least some
DNA or
RNA involved, never a
parasiting protein) it is not likely you’re going to find it easily.
IV. Results tend to be in the direction that the
conformation change apparently happens on a
membrane in the cell interior. Apparently in neurons. They accumulate in the
lysosomes in the cell, which will burst and then infect other cells. The
plaques mentioned in the previous write-up are not always observed, nor that it disturbs
intracellular processes per se. See also next point V.
V. There is a suspicion of the existence of prion “strains”, multiple possible conformations of prions. This is based on the idea: hey, we’ve found two conformations, if there are two, it makes sense if there are more, and that would explain the different results seen (disease
symptoms,
location of the prions in the body.)
What they really don’t know
(or I just couldn’t find the answer)
A. All research seems to be directed towards the harm the prions can do, but the PrPc variant is produced in a lot of animals, which indicates that the gene sequence is
evolutionary old. Does this mean that PrPc is also
beneficial to the body? Why is it produced in the first place? Involved in
synaptic functions? (See points II and 4)
B. After
transcription and
translation of the PrPc, there are extensive
post-translational modification (mainly conformational changes) made to the protein, meaning that the protein is “advanced and evolved”. How does that happen? What exactly is changed, and what is the
sequence of these events?
C. Pigs, chicken, sheep and farmed fish all have been exposed to BSE-contaminated feed. But what is the difference in the DNA and
tertiary structure of the prions? And I don’t mean the answer that there are 30 different positions between bovine and human prions, or the 7 between sheep and cows, I know that. But some parts of the protein are less important for functioning than others. Are those differences in supposed
active sites of the prion? The disease pattern in humans tend to be more similar to sheep, so do sheep infect humans more easily? (Side note: currently there doesn’t seem to be a “consistent
correlation” between countries herding and eating a lot of sheep and CJD, but see also next point) And if the transmission pattern thought to be similar, what about
blood transfusions? (This is being investigated now)
D. If the sheep fed with BSE-contaminated meat can pass on their prions to mice, can they do that to humans too? And if yes, are the symptoms similar to scrapie, or BSE, or something else we don’t know yet? I don’t want to be highly
suggestive, but take a disease like
Alzheimer: physiologically the brain gets porous in a relatively similar way like CJD, leading to the question: Are they both related to prions or prion-like molecules?
E. PrPsc
catalyses the conformation (only? And alone?) change from the á-helix in PrPc into the ß-sheet in PrPsc. But initially only “harmless” PrP is produced. There must have been a first
flipping prion. Produced by the body itself, e.g. that the post-translational machinery doesn’t work properly anymore? Was the protein PrPc getting “old” and changed conformation? To which extend is it possible for a PrPsc from say a cow to
induce the flipping of PrPc in humans (or whatever other test animal) (see point I)?
F. They don’t know the
process during the
conformation change.
Still a lot of
uncertainties, like with most
natural science research. But that’s also its charm… well, for people who like to dig into the topic of course. If anyone knows more, or even has answers on the above questions, please node them.
Most information is from articles from
New Scientist,
Scientific American and
Nature. A well-written resource that also provides insight in “their search for truth” is the article at http://www.nmia.com/~mdibble/prion.html.
The Alchemist informed me about http://www.mad-cow.org/, that info probably will be added in the near future.
Other E2 nodes related to this topic: Kuru, mad cow disease, spongiform encephalitis, scrapie, scrapies, BSE, bovine spongiform encephalopathy, Creutzfeld-Jacob disease, CJD, Creutzfeld Jacob disease (CJD), mad pig disease.