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 suspect
ed and speculate
d, and I’ll end with some remaining question
s. The aspects per section are mentioned in pretty much of a random order.
What they think they know
A prion is a proteinaceous infectious particle and can induce spongiform encephalopathies
in a lot of animals, not only sheep (scrapie
) and humans
), but also rodents, minks (TME
), elks (CWD
) and probably pigs, chicken and some farmed fish.
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.
variant of the prion is called PrPc
article cellular), the harmful
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 cell
s, 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 synaps
es 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
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.
s affect different specie
s in different ways. The result can be no symptom
s, 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-contaminate
d feed, they develop a disease clinical
ly similar to scrapie. But when their meat is fed to mice, the mice develop BSE symptoms. Further, BSE tends to affect the brain
s primarily, whereas the PrPsc in sheep can be found all over the body.
What they suspect
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
normally involved in folding nascent protein
chains, recognized one or both mouse-derived regions of the PrPc.
PrPc is predominantly found on the surface of neurons, attached by a glycoinositol phospholipid
anchor. What is its purpose there? (See also 4)
ed 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
s 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 cell
s 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
es, at least some DNA
involved, never a parasiting
protein) it is not likely you’re going to find it easily.
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 lysosome
s in the cell, which will burst and then infect other cells. The plaque
s mentioned in the previous write-up are not always observed, nor that it disturbs intracellular
processes per se. See also next point 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 symptom
of the prions in the body.)
What they really don’t know
(or I just couldn’t find the answer)
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 function
s? (See points II and 4)
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?
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 site
s 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 transfusion
s? (This is being investigated now)
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?
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 flip
ping 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)?
They don’t know the process
during the conformation
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
. 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.