shootingstar21 at hotmail.com wrote in message
<783vt3$jco$1 at nnrp1.dejanews.com>...
>How sound is the prion hypothesis by Stanley Prusiner and how exactly does
a
>normal protein change into a shape that can cause disease and distort other
>normal proteins into the "bad" shape? Also, specifically, what is the
>experimental evidence for the prion hypothesis and what are the new
>developments, if any, in the theory and in finding cures for prion
diseases?
>
I looked into the prion diseases during my honours year, and was taught by
one of the members of the Gov advisory committee for the BSE "crisis". Hmm.
Anyway...
The current prion hypothesis is broadly as you describe above - one type of
a protein somehow turns other proteins of SIMILAR sequence but DIFFERENT 3D
shape into it's own 3D shape. The evidence?
Well, there are definitely two different forms of the prion protiens (PrP)
found in prion diseases. Only one sort is found in normal tissues. The
physical differences are that the abnormal sort cannot be cut up by certain
enzymes, cannot dissolve, and is made up of "sheets" of atoms rather than
"spirals".
When you add some of the altered protein to normal tissues disease results
and you get more of the abnormal protein. It certainly looks like there's
some sort of alteration being done. It CAN'T be replication of the protein.
That needs DNA or RNA, and there isn't enough in the prions to do that.
Furthermore the altered protein that is made is from the host.
Example. A sheep gets scrapie. You collect the prions from the sheeps
brain, and analyse it. It contains sheep PrP of the altered form. Put it
into a mouse. The mouse gets scrapie. Extract the prions and analyse them.
They are made up of MOUSE PrP. Scary.
How does it do it? No-one's really sure. The only experiments I know of
haven't been exactly promising. While they _can_ get the PrP to change
shape, it's only using vast excessess of abnormal PrP compared to normal
PrP. However, the sort of changes that occur have been worked out, and
while the _whole_ protein doesn't change it's shape very easily, if you cut
it up into bits it does! It's obvious that the protein isn't cut up into
bits and then put back together again, but it's possible that another
protein (called a chaperone) somehow helps this reaction to take place. The
very first prion to be discovered, in yeast, has exactly this mechanism. No
proof exists (AFAIK) to support this theory in mammals.
What is _really_ weird is that is you put sheep PrP into a mouse you get a
_different_ disease than if you put cow PrP into a mouse. WHY??!! Again
no-one knows - it's almost as if the sheep PrP is changing the mouse PrP to
a different shape than the cow PrP does. It sounds bizarre, but there's no
denying the fact that there are "strains" of prions. They can even be
propogated in the lab.
Example. Put sheep PrP into a mouse. It gets scrapie.
Put cow PrP into a mouse. It gets BSE.
Put cow PrP into a sheep, then put the sheep PrP into a mouse. It gets BSE.
But remember that the PrP that went into the third mouse was made from
sheep! How does the sheep PrP give the same disease as cow PrP? It must be
propogating some sort of characteristic - it can't be sequence, so it must
be shape...
Incidentally that was the major evidence suggesting that BSE had spread to
humans. The human new variant of CJD looked exactly like BSE in mice. Same
disease process, same bits of the brain affected, same timescale. Normal
human CJD looks quite different in mice.
IE Put cow PrP into a mouse. It gets BSE
Pur human PrP into a mouse, it gets CJD.
Put cow PrP into a human, then put human PrP into a mouse. It gets BSE.
The thing is there is a MASSIVE species barrier, probably due to the
different sequences of the proteins in the different species. It takes 1000
times the dose of prions to infect a mouse as it does to infect a cow.
Imagine 1gram of prions infecting a cow. Imagine a kilogram of prions
infecting a mouse! Messy. (The numbers aren't that big by the way, but you
get the idea).
Prusiner himself has actually said that he doesn't think the nvCJD was due
to BSE, since there were so few cases (30-odd I think by now). He's
ignoring the species barrier, and the experimental evidence I think. It all
points to nvCJD being of the same strain as BSE. It's _possible_ they're
completely unrelated, but if it looks like a duck, and quacks like a duck...
New developments? The most recent work I know of (which is several months
old by now) has outlined using small bits of protein to try to interfere
with the accumulation of the abnormal PrP. It works in rats!!!! It was
actually meant as an Alzheimers therapy trial, but they extended it to
include other protein-accumulation diseases. I've heard nothing since,
mainly because I've been away from the literature for a while. I might come
to something.
Hope that was useful.
Cheers
Bennett