why Alzheimers is not prion disease; table of similarities/differences
Archimedes Plutonium
the coating is a protein also?
> You wrote:
> > Several mechanisms are known for ways to avoid proteosome degradation,
> > most of them used by viruses. One way would be to make to proteins
> > insoluble, like those in Alzheimers and prion disease (yes
> > you're right, the two are very similar).
Archimedes Plutonium
newsreader, or is someone cancelling your posts? The below I had to
retrieve Dejanews.
Bennett, I please need your help in telling me the differences and
similarities between Alzheimer's and prion diseases. Logic does say
they should be the same and derive from the same mechanisms. Logic
could have it that prion disease mechanism is altogether different from
Alzheimers, but when faced with so many similarities, logic suggests
that the two diseases have the same underlying chemistry modus
operandi.
Is the plaque in Alzheimers at all related to CJD?
Is the Alzheimers plaque protease resistant?
Do sheep and cattle get Alzheimers?
You wrote:
> Several mechanisms are known for ways to avoid proteosome degradation,
> most of them used by viruses. One way would be to make to proteins
> insoluble, like those in Alzheimers and prion disease (yes
> you're right, the two are very similar).
Someone wrote and said that the genetics of Alzheimers is worked out.
If true, then how does the genetics confer protein insoluble to
Alzheimers?
Bennett, if you were a biochemist design engineer. How would you design
a viral additive to a prion protein to make it protein insoluble?
Instead of making a table of rates, I need to make a table of
comparisons between Alzheimers and Prion Diseases.
Bennett, Pelletier gave this as a summary of prion disease:
> Shape change --> protease resistance --> slower degradation -->
> Accumulation of protein.
What kind of summary is there for Alzheimers ? Would it go like this
mutation on a gene --> protease resistance --> slower degradation -->
accumulation of Alzheimer plaque
Bennett, please fix it so that your posts appear on the newsreaders.
Thanks
Re: Deciding experiment of Prusiner's prion
disease
Author: Bennett <nj...@spam.ac.uk>
Date: 1999/03/14
Message-ID: <7ch0d9$dva$1...@pegasus.csx.cam.ac.uk>
Newsgroups: sci.med,sci.bio.misc,sci.bio.technology,sci.chem
Organization: University of Cambridge, England
References:
<7bhafi$345$1...@dartvax.dartmouth.edu>
<36e30863...@agate.berkeley.edu>
<7c1dne$ng5$3...@dartvax.dartmouth.edu>
<7c2u73$lqa$1...@pegasus.csx.cam.ac.uk>
<7c589a$qj6$2...@dartvax.dartmouth.edu>
<7cbim2$a7h$1...@pegasus.csx.cam.ac.uk>
<7cc6c5$tl5$1...@dartvax.dartmouth.edu>
Archimedes Plutonium wrote in message
<7cc6c5$tl5$1...@dartvax.dartmouth.edu>...
>In article <7cbim2$a7h$1...@pegasus.csx.cam.ac.uk>
>"Bennett" <nj...@spam.ac.uk> writes:
>
>> I'm afraid that your DNA changes and tRNA theories are wrong - you don't
>> seem to _really_ know what tRNA does, despite my brief explaination. I'm
>> not sure if it's worth persevering with you any more...
>
> Please, do not break away. I need your information of rates and
>numbers data of the various prion diseases. I realize that you and Bob
>and Tony and others entered into these discussions with the intent of
>brainwashing me into accepting the Prion Disease as a shape/form
>disease and to waste away 30 years in the loopy logic of form/shape.
Not at all - but it does appear as if there's been a misunderstanding.
You would be surprised at how long it takes for a
>mind in search of understanding to come to the conclusion that it is
>*quantity* that drives this disease, not the qualitative shape and
>form.
Here it is! Yes, we have been prattling on about the changes in shape,
but
we've known already that the disease is due to the plaques of PrPres
accumulating in the affected brains, we just haven't said so.
Apologies,
since this was obviously not made clear. The PrP does indeed
accumulate,
and the early experiments set out to find out why. The results they
got
suggested only that the PrP had changed shape.
>
> Here are a few questions that came to my mind as I wrote:
>
>(1) Are there any accompanying elements or other proteins in excess,
>along with the prion proteins. That is, in Prion Diseases such as CJD,
>scrapie, mad-cow, do we only see a overpopulation of prion proteins, or
>do we have other elements such as another protein or water or
>carbohydrate or fatty acid buildup. I want to know if the Prion Disease
>is buildup of only prion proteins and nothing else?
>
The infectious units are mostly PrP - any DNA they contain seems to be
irrelevant. The actual plaques might contain other things but I don't
know.
>(2) Which of the prion animal diseases is the most genetic or
>hereditary of the prion diseases? Is it GSS or FFI? The reason I ask is
>because this disease should be the least dangerous to work with, and
>this particular prion disease should be the best in finding out the
>actual genetic mutation for the manufacturing site of the prion disease
>protein. Once we find the mutation site, our progress should advance
>quickly.
>
I think GSS is the best, it's better defined I think. The mutations
are
know, but they're within the coding region of the gene, not the
regulatory
regions (IIRC). They seem to make the protein flip more easily to
PrPres
from PrPsen. PrPres is not made automatically, but statistically a
rogue
molecule must appear at some point.
>(3) Here I suspect from (2) that the Kuru disease was a isolated
>incidence of CJD in that the Kuru Indians were a isolated tribe and
>their genetics were so similar.
Hmmm. The thing is that Kuru was wiped out from the tribe as soon as
they
stopped eating each other's brains. Yes, that's what they did.
Someone
died from CJD, everyone eats a bit of the brain to gain their wisdom -
someone else dies from CJD, and so on. Stop eating brains...CJD (Kuru,
same
thing) disappears...
Thus being so much alike in heredity
>since the tribe was so closely in-bred that the occurrence of one prion
>disease victim would result in an epidemic. Interpretation: it is not
>that the prion proteins are so infectious, but rather, that the genetic
>mutation of the Kuru Indians was so widespread and prominent in their
>population. That the prion proteins were not infectious but rather
>served to *activate the already existant mutated genetics*.
>
AFAIK the tribe did not have a PrP mutation.
<snip rest>
Sorry, I haven't the time to talk through these, and I'm not sure
they're
directly relevant to the molecular biology ;-) Suffice to say that
inbreeding itself won't cause prion disease, but diversity is better.
There
are some sheep breeds which are much less resistant to scrapie than
others,
and the species barrier between mice and cows is high. I suspect it is
between cows and humans as well, and I don't expect there to be a
massive
epidemic of nvCJD, as prophesised by some people a few years ago. Of
course
back then we had no idea, but with only 30 or so cases out of God knows
how
many beef eaters.....I'm not convinced it'll happen. The incubation
period
seems to be about 5 years, we should peak in 2001 or thereabouts.
Now, I'll sit back and wait to be proven wrong ;-) I sincerely hope
I'm
not!!
Cheers
Bennett
--------------------------------------
Re: Scoreboard of Prion Diseases
Author: Bennett <nj...@spam.ac.uk>
Date: 1999/03/14
Message-ID: <7cguke$cdb$1...@pegasus.csx.cam.ac.uk>
Newsgroups: sci.med,sci.bio.misc,sci.bio.technology,sci.chem
Organization: University of Cambridge, England
References:
<7c7fpl$a3a$1...@dartvax.dartmouth.edu>
<7c7h7u$7d0$1...@dartvax.dartmouth.edu>
<7ca85j$ri1$1...@dartvax.dartmouth.edu>
<36E97E90...@scripps.edu>
<7cc3di$rb0$1...@dartvax.dartmouth.edu>
Archimedes Plutonium wrote in message
<7cc3di$rb0$1...@dartvax.dartmouth.edu>...
>In article <36E97E90...@scripps.edu>
>"Anthony J. Pelletier Ph.D." <anth...@scripps.edu> writes:
>
>> So the first question is: "is there more of the prion protein in cells
>> of affected individuals than in non-affected individuals?" The answer
>> is "yes!"
>
> So there, my theory is correct, end of prion disease theories.
Don't rush in yet...
>
>> buffer and export out of the nucleus. This in itself has several steps,
>> which we will treat as one and simply ask: "is there more mRNA?" It
>
>
> No, Tony. The logical question does not ask for more mRNA. For the
>overproduction of the protein can occur further down in manufacturing
>cycle, specifically in the tRNA and the proteins that tell the
>machinery to Halt or Stop production.
The thing is that the rate-limiting step is the number of mRNA's being
made.
The tRNA's exist in vast excess and have no control over how many
proteins
they contribute to.
No need to match numbers of mRNA
>with the numbers of oversupply of prion proteins. You sound as if there
>is a one-to-one correspondence between numbers of proteins to number of
>mRNA. It does not work that way.
>
Err, I think you'll find it does, more or less. Not 1/1 maybe, but
perhaps
2 or 3 copies of protein per mRNA. Doubling the mRNA production will
double
the protein production.
> Granted, my knowledge of actually producing a prion protein molecule
>is sketchy at best. What I am after is the site where a prion protein
>molecules are made in excess. Whether this excess site is mRNA or tRNA,
>I do not know. I do know that the proteins tell the mRNA or tRNA to
>Halt or Stop the making of some molecules, and of course, prion
>proteins could serve this function as a Halter or Stopper.
>
> Someone said the function of prion proteins was for 'cell wall
>material'.
Well, that's where they're found in normal cells. They're nowhere near
the
protein production centres and won't be able to control protein
synthesis in
the way you're describing.
But I believe the function for prion proteins is to be the
>actual Halter or Stopper of protein production. Or, at the other end,
>the Starter Codon for protein production and in the case of Prion
>Disease, the site of prion proteins is mutated to overproduce prion
>proteins.
As we've said before, the gene encoding PrP does not alter, and that
includes its regulatory domains. It's exactly the same gene, producing
exactly the same protein sequence, but that protein is somehow changed
after
production and it exhibits characteristics as if it had changed shape.
Cheers
Bennett
-------------------------------------------------
Re: Mechanism that generates prion
disease; cure and treatment
Author: Bennett <nj...@spam.ac.uk>
Date: 1999/03/14
Message-ID: <7cgu7e$bvl$1...@pegasus.csx.cam.ac.uk>
Newsgroups: sci.med,sci.bio.misc,sci.bio.technology,sci.chem
Organization: University of Cambridge, England
References:
<7c832g$fut$1...@dartvax.dartmouth.edu>
<7cbi95$a23$1...@pegasus.csx.cam.ac.uk>
<7cc23f$uir$1...@dartvax.dartmouth.edu>
Archimedes Plutonium wrote in message
<7cc23f$uir$1...@dartvax.dartmouth.edu>...
>In article <7cbi95$a23$1...@pegasus.csx.cam.ac.uk>
>"Bennett" <nj...@spam.ac.uk> writes:
>
>> No - the answer seems to be that the PrPres accumulates as insoluble muck
>> rather than normal PrPsen. There's no evidence that I know of to suggest
>> that the PrP is made in greater quantity, and it isn't any different from
>> the abnormal form in any respect apart from its structure.
>>
>> The DNA sequence is unaltered, the protein sequence is unaltered. The
>> protein simply congeals.
>
> Bennett, you wrote a contradiction. It is quantity of prion protein
>the kills the host. Not whether it congeals or changes form or dances.
As Tony outlined in his reply, I was correct.
>
> Question: Would a CJD victim die of prion disease if all of its prions
>were in good prion form?
No.
You seem to think that quantity makes no
>difference and that the killer is the bad prion form. You seem to think
>that form/shape is the killer. It is not. It is the quantity of
>protein, no matter what form it is in.
>
There's no evidence of that at all, and all the evidence points to the
idea
that accumulation of congealed, non-degraded PrP leads to prion
disease.
> Please try to answer that question, Bennett, would a sheep die of the
>disease given the quantity of prions, no matter what shape they are in?
>Would a cow of mad cow disease die of the disease no matter which one
>of your alphabet soup PrP you care to inject? Same question for humans.
>If you are honest with your science, you would know that the answer is
>yes,
I'm honest with my science, since I have honestly never seen or heard
of
any
data backing that assumption.
---------------------------------------
Scoreboard of Prion Diseases
Author: Bennett <nj...@spam.ac.uk>
Date: 1999/03/14
Message-ID: <7cgves$d2n$1...@pegasus.csx.cam.ac.uk>
Newsgroups: sci.med,sci.bio.misc,sci.bio.technology,sci.chem
Organization: University of Cambridge, England
References:
<7c7fpl$a3a$1...@dartvax.dartmouth.edu>
<7c7h7u$7d0$1...@dartvax.dartmouth.edu>
<7ca85j$ri1$1...@dartvax.dartmouth.edu>
<36E97E90...@scripps.edu>
<7ccq9c$62d$1...@dartvax.dartmouth.edu>
<7cd3s4$atq$1...@dartvax.dartmouth.edu>
<7ceufe$3ac$1...@dartvax.dartmouth.edu>
Archimedes Plutonium wrote in message
<7ceufe$3ac$1...@dartvax.dartmouth.edu>...
>In article <7cd3s4$atq$1...@dartvax.dartmouth.edu>
>Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
>
>> Pelletier wrote:
>>
>> > Shape change --> protease resistance --> slower degradation -->
>> > Accumulation of protein.
>>
>> Okay, that may put a serious wrinkle into my theory
>>
>> my theory would go like this:
>>
>> increased rate of production of prion protein, regardless of shape -->
>> accumulation of protein, regardless of shape --> death upon a certain
>> level of accumulation
The evidence to date suggests that the PrP in prions is only of the
altered
state, and that altered state is never found in normal tissues.
>
> Questions:
>(1) when an animal dies of prion disease, is there only an accumulation
>of the protease resistant prion proteins PrPres? No accumulation in any
>of the other prion proteins?
>
Not that has been detected.
>(2) when an animal mRNA gets done manufacturing the prion protein, what
>happens to the mRNA molecule itself?
>
The mRNA molecule is inherently unstable - some might even get degraded
before being used. Some might last to produce several copies of their
encoded protein. AFAIK the bonds are simply hydrolysed (reacted with
water
and split) and the individual nucleotides reused in another RNA
molecule.
>(3) could the PrPres be a combination of the normal prion protein plus
>some of the mRNA debris or snippet?
Possible, but as mentioned many times before that snippet would have to
withstand serious UV degradation. RNA is less stable than DNA and
easily
degrades anyway. The PrP does not have a RNA/DNA binding domain. The
evidence goes against that as being relevant to prion disease.
>
> By logical sense, it seems too awkward of a situation that a bad
>prion protein can change the shape of a normal prion protein via a weak
>hydrogen bond and yet this weak hydrogen bond is so strong as to resist
>protease action. Seems to me like a logical contradiction that you have
>a weak hydrogen bond for changing shape/form yet this weakness is a
>strength in the face of protease action.
>
A reasonable point. The difference is that this H-bond isn't merely
holding
back the protease action, it's holding the protein is a 3D arrangement
that
cannot fit into the degradation machinery. This machery is called the
proteosome. It's a LARGE molecule made up from several different
proteins
that looks a bit like a tunnel. Proteins go in one end and come out
the
other all chopped up. It is an essential part of the immune system (it
helps present viral and some bacterial proteins to the T cells for
recognition and attack!) Several mechanisms are known for ways to
avoid
proteosome degradation, most of them used by viruses. One way would be
to
make to proteins insoluble, like those in Alzheimers and prion disease
(yes
you're right, the two are very similar).
I hope that explains it for you.
Cheers
Bennett
Archimedes Plutonium
Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> Bennett, Pelletier gave this as a summary of prion disease:
>
> > Shape change --> protease resistance --> slower degradation -->
> > Accumulation of protein.
And it is rather sad, and funny, how one can read nearly all of the
science literature on Prion Disease, such as SCIENTIFIC AMERICAN and
still not understand the disease as what is encapsulated in the above
summary. It took me 2 months of debating on the Internet until that was
clear in my mind. This is a sad reflection on science education, that
we can print kilograms on prion disease yet the clear understanding of
the disease such as in the above one sentence is never there.
Bennett
> Bennett, are you doing a no-see-um on your posts, none appear on my
>newsreader, or is someone cancelling your posts? The below I had to
>retrieve Dejanews.
Sorry - nothing to do with me. I've noticed the same with some other posts
in the past from other people.
>
> Bennett, I please need your help in telling me the differences and
>similarities between Alzheimer's and prion diseases. Logic does say
>they should be the same and derive from the same mechanisms. Logic
>could have it that prion disease mechanism is altogether different from
>Alzheimers, but when faced with so many similarities, logic suggests
>that the two diseases have the same underlying chemistry modus
>operandi.
>
Okay, the similarities have indeed made people ask these questions.
> Is the plaque in Alzheimers at all related to CJD?
No. The PrP is not found in the Alzheimers plaques, it is a different,
unrelated protein.
> Is the Alzheimers plaque protease resistant?
I'm afraid I don't honestly know. As far as I can tell the amyloid plaques
in Alzheimers are simply accumulations of a protein which is unalterred from
its normal state. It is produced in response to cell death and damage.
This damage is actually the cause of the disease (the plaques are a result,
but can contribute as well). The primary damage seems to be due to
neurofibrillary tangles, made from a _different_ protein yet again. I don't
know enough about it to comment much further. Suffice to say that over
production, or reduced degradation of the plaque protein have all been shown
to be important in Alzheimers.
> Do sheep and cattle get Alzheimers?
>
I don't think so, but then I'm not a vet ;-)
>You wrote:
>> Several mechanisms are known for ways to avoid proteosome degradation,
>> most of them used by viruses. One way would be to make to proteins
>> insoluble, like those in Alzheimers and prion disease (yes
>> you're right, the two are very similar).
>
> Someone wrote and said that the genetics of Alzheimers is worked out.
>If true, then how does the genetics confer protein insoluble to
>Alzheimers?
>
The genetics seem to be linked to the degradation of the plaque protein
(IIRC). When any protein accumulates too much it can turn into amyloid, a
sort of gunky stuff.
>Bennett, if you were a biochemist design engineer. How would you design
>a viral additive to a prion protein to make it protein insoluble?
>
I don't know. My limited knowledge on protease-resistance says that the
resistance is either due to the protein sequence or the 3D structure. I
cannot change the protein sequence externally (although I could mutate the
gene and start from scratch). Changing the 3D structure seems possible (its
the entire basis for the protein-only theory) but I wouldn't know where to
start to _design_ such a mechanism.
> Instead of making a table of rates, I need to make a table of
>comparisons between Alzheimers and Prion Diseases.
>
> Bennett, Pelletier gave this as a summary of prion disease:
>
>> Shape change --> protease resistance --> slower degradation -->
>> Accumulation of protein.
>
> What kind of summary is there for Alzheimers ? Would it go like this
>mutation on a gene --> protease resistance --> slower degradation -->
>accumulation of Alzheimer plaque
>
Hmmm. I think it's more like
Neurofibrillary tangles->cell death->plaque protein released->over
production leads to amyloid
With a feedback loop built in such that plaque protein also leads to cell
death.
But I may be simplifying it too much...
Cheers
Bennett
Micheal
) I pound his male rectum.
) Penis could mature him.
) Mr. Meticulous Pinhead.
) Champion tedium rules.
) Oh, supreme dim lunatic.
) Posh, numerical tedium!
) Plutonium? Scream - hide!
) The delicious rump man.
) Tiresome unlaid chump.
) Demonic mailer, shut up!
) Oh, I'm presumed lunatic.
) I am the purloined scum.
) A much rude simpleton, I.
) Me, I am one stupid churl.
) Humanoid rectum piles.
) Supreme Homicidal Nut.
) comp.uranus.let.him.die.
) Cute malnourished imp.
) Out, impure Mensa child.
) Mouse dimple cunt hair.
) Aluminium copter shed.
Archimedes Plutonium
"Bennett" <nj...@spam.ac.uk> writes:
> I don't know. My limited knowledge on protease-resistance says that the
> resistance is either due to the protein sequence or the 3D structure. I
> cannot change the protein sequence externally (although I could mutate the
> gene and start from scratch). Changing the 3D structure seems possible (its
> the entire basis for the protein-only theory) but I wouldn't know where to
> start to _design_ such a mechanism.
I want to start with normal PrP and build into it these functions
such that my final product is bad PrP:
functions designer model into normal PrP
(1) a snippet of DNA/RNA whose role was to build the protein coat on
the virus/fungus, and, attached to this DNA/RNA is a snippet of the
protease resistant protein coat.
(2) this protein coat is very elaborate and comes equipped with viral
sensors that is able to rearrange the shape/form of a normal PrP
whenever it comes into contact with a normal PrP. I believe the HIV
virus, for example is equipped with this fancy sensors and molecular
scissors to rearrange a normal cell.
(3) Call this snippet of DNA/RNA with its attached snippet of protein
coating the IA for Infective Agent.
(4) The coating is protease resistant and protects the DNA/RNA snippet
from UV.
(5) IA is protease resistant and when IA contacts a normal PrP its
protein coat cuts into the PrP allowing the DNA/RNA to become a
integral part of the PrP and its instructions on the DNA/RNA possess
the desire to create more of the protein coat.
(6) Whenever a normal PrP comes into contact with the IA of the bad
prion protein, the coating has the sensory equipment to change the form
and shape of the good PrP into a protease resistant bad PrP
(7) Only the IA bad PrP can change the shape/form of a normal PrP
(8) The IA can jump ship from one PrP that it has changed its
form/shape or remain attached to one PrP
Bennett, I believe a good starting out experiment using the
designer-model methodology would be to take a batch of protease
resistant viruses and to cut them to pieces and then inject those
pieces into a batch of normal PrP and then inject this batch into a
normal animal such as hamster or mice and see if a Prion Disease
develops.
Also, it is suggested that Chlamydia viruses cause Alzheimers disease.
You wrote:
> Neurofibrillary tangles->cell death->plaque protein released->over
> production leads to amyloid
>
> With a feedback loop built in such that plaque protein also leads to cell
> death.
>
> But I may be simplifying it too much..
Perhaps if we again use this Designer-Model methodology and take some
Chlamydia viruses and cut them into pieces, their coatings and all, and
then put them into a batch of normal cells and see if neurofibrillary
tangles start to arise.
Archimedes Plutonium
Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> (1) a snippet of DNA/RNA whose role was to build the protein coat on
> the virus/fungus, and, attached to this DNA/RNA is a snippet of the
> protease resistant protein coat.
> (2) this protein coat is very elaborate and comes equipped with viral
> sensors that is able to rearrange the shape/form of a normal PrP
> whenever it comes into contact with a normal PrP. I believe the HIV
> virus, for example is equipped with this fancy sensors and molecular
> scissors to rearrange a normal cell.
> (3) Call this snippet of DNA/RNA with its attached snippet of protein
> coating the IA for Infective Agent.
> (4) The coating is protease resistant and protects the DNA/RNA snippet
> from UV.
> (5) IA is protease resistant and when IA contacts a normal PrP its
> protein coat cuts into the PrP allowing the DNA/RNA to become a
> integral part of the PrP and its instructions on the DNA/RNA possess
> the desire to create more of the protein coat.
> (6) Whenever a normal PrP comes into contact with the IA of the bad
> prion protein, the coating has the sensory equipment to change the form
> and shape of the good PrP into a protease resistant bad PrP
> (7) Only the IA bad PrP can change the shape/form of a normal PrP
> (8) The IA can jump ship from one PrP that it has changed its
> form/shape or remain attached to one PrP
Speaking of another *rate* from the above scenario. That scenario
implies a rate of the foreign virus/fungus of so to speak cutting into
the normal prion protein and decoupling its bonds in order to reshape
and reform the prion protein into PrPres. I contend that this changing
of shape/form is easiest and straightforwardly done by a virus sensory
receptors on its protein coating.
Below, both Bob Bruner and Tony Pelletier discuss briefly the
complexity of these bonds that are broken in order to reshape and
reform PrPsen into PrPres. I contend that the best candidate of a
mechanism to cut into a PrPsen and then to reshape and reform PrPsen
into that of PrPres.
Could someone please elaborate for me how easily a virus sensory
receptors are able to cut-into a protein molecule such as PrPsen and
once cut into, how easily that viral equipment can then reform and
reshape the PrPsen molecule into a tightly-wound PrPres.
Also, someone expert on knowing the details of viral sensory
receptors and cutting-equipment and someone expert on PrPsen structure
would be able to roughly point at a particular family of viruses or
fungus whose *sensory equipment* would most easily do the job of
reforming PrPsen into PrPres.
Below is a repeat of Bob's and Tony's post on the bonds that must be
broken and then reformed. For the PrPres molecule that is so very
identical to PrPsen molecule to perform that feat strains gullibility.
But for a virus to break those numerous bonds and then reshape the
molecule is routine business. In fact, viruses live for just that
assignment
In article <36ec5c34...@agate.berkeley.edu>
bbr...@uclink4.berkeley.edu (Bob) writes:
Well, this is a somewhat distorted view of the conversion. It is not a
single H-bond, but a collection of them.
Analogy... The difference between single stranded (SS) DNA and double
stranded (DS) DNA is a collection of hydrogen bonds between the two
strands in the DS form. That _collection_ of hydrogen bonds, hundreds
of them in even a small piece, holds the strands together strongly
enough that one has to add considerable energy to separate the
strands. One enzyme well known to molecular biologists can degrade SS
DNA, but not DS -- and the only difference is that set of hydrogen
bonds. (If I recall, the enzyme works about 75,000 times faster on SS
DNA than on DS.)
As someone noted, much degradation of proteins is done within a cage,
and the bad prion, aggregated, undoubtedly does not fit in the cage.
However, I think it is also intrinsically resistant to proteases,
presumably because critical sites are no longer exposed.
In article <36ED32C2...@scripps.edu>
"Anthony J. Pelletier Ph.D." <anth...@scripps.edu> writes:
Well, there they are, but I doubt it will help.
As for the last paragraph, you don't understand the chemistry of
proteases well enough.
The hydrogen bonds are not the ones cleaved by proteases, the amide
bonds, which are covalent, are.
Protein folding involves a lot more than just hydrogen bonds, though
they are important.
The question is, in the overall folded structure, can the protease get
access to the amide bonds?
Here's a simple question: how do proteases, which degrade proteins,
exist at all? Why don't they degrade each other?
So, in order for proteases to work, they need to get part of the
protein
they are degrading into their binding pocket more or less straightened
out, so that the active site can get access to the amide bonds. If the
protein is folded extremely tightly, with no exposed strands, it's hard
for the protease to get hold of it.
That's a crude explanation, but I would be happy to provide a more
detailed reference, if you want.
Archimedes Plutonium
Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> Also, someone expert on knowing the details of viral sensory
> receptors and cutting-equipment and someone expert on PrPsen structure
> would be able to roughly point at a particular family of viruses or
> fungus whose *sensory equipment* would most easily do the job of
> reforming PrPsen into PrPres.
I also wrote in another article that the Chlamydia pneumonia bacteria
is implicated in Alzheimers disease. Now, here is a possible
unification of Alzheimers to Prion diseases. If the culprit in both
diseases is a snippet of the virus/fungus/bacteria protein coat and
even a snippet of the DNA/RNA of the virus/fungus/bacteria.
I believe, although I do not know, and perhaps Tony will quickly come
to the rescue by saying that there exists such a field of study.
Anyway, I am going to suggest that there exists no hard core field of
science study of virus, fungus, bacterial debris in the body of the
host. And that a science field should be created whose objective is to
study the debris of these foreign invaders into the body and to trace
and catalog what that debris is and how it moves through the body and
passed out of the body.
I suspect there is no such field of science and that the knowledge of
this subject is kept with the knowledge of those particular viruses or
fungus that catch our attention. And that many scientists neglect what
happens to the debris of these foreign invaders of the body. If my
model of prion disease and Alzheimers is correct, would imply that both
of these diseases are caused by debris of a foreign invader such as a
virus.
It is usually the case that when a human kills another human it is
via the arrow or the gun bullet or the missile that the human sends the
other. Likewise, the nucleic acid of a virus, or fungus or bacteria may
not kill the host but the debris such as protein coating and coating
sensory equipment that causes the disease in the host.
If there is not a formal science on this already, what would be a
good name for the science study of the material shed by a parasite?
Parasite Byproducts?
Archimedes Plutonium
> Hmmm. I think it's more like
>
> Neurofibrillary tangles->cell death->plaque protein released->over
> production leads to amyloid
>
> With a feedback loop built in such that plaque protein also leads to cell
> death.
>
> But I may be simplifying it too much...
I would like to make some inroads, at least, into the unification of
Alzheimers disease to that of prion diseases. And even already I made a
mistake by calling Chlamydia a virus, when it is a bacteria. My memory
is failing me on these facts.
> Unlike most bacteria, C. pneumoniae lives inside cells. While it
> hasn't been found in the brain before, scientists could have mistaken
> the microbe for cellular structures known as lysosomes, argues Balin.
> Moreover, it infects brain cells called glia rather than the nerve
> cells that die in Alzheimer's disease.
> When glia are infected, they may produce immune molecules that
> ultimately harm
> neighboring nerve cells. "We think it's the inflammation that's really
> doing the damage," says Balin.
> --- end quoting Science News, November 21, 1998, p. 325 ---
So, perhaps the C. pneumonia bacteria causes inflammation that causes
Neurofibrillary tangles.
Bennett, are these tangles reshaped and reformed and are they
protease resistant?
And does C. pneumonia have protein coats and these protein coats are
shed when the bacteria enters the cells? And do these coats of the
bacteria have sensory equipment that can bind/ligand with the
Neurofibrillary tangles molecules?
Bob
(Archimedes Plutonium) wrote:
> Also, someone expert on knowing the details of viral sensory
>receptors and cutting-equipment and someone expert on PrPsen structure
>would be able to roughly point at a particular family of viruses or
>fungus whose *sensory equipment* would most easily do the job of
>reforming PrPsen into PrPres.
>
Don't need a virus etc. This a perfectly reasonable thing for the
protein to do all by itself. Proteins change shape all the time. On a
large scale (forming polymeric forms)... muscle proteins or
microtubules, yes?
> Below is a repeat of Bob's and Tony's post on the bonds that must be
>broken and then reformed. For the PrPres molecule that is so very
>identical to PrPsen molecule to perform that feat strains gullibility.
only to people not knowledgeable about proteins!
Why not go discuss protein shape issues with a local biochemist, or
maybe even sit in on a basic biochem course.
bob
Archimedes Plutonium
bbr...@uclink4.berkeley.edu (Bob) writes:
> Don't need a virus etc. This a perfectly reasonable thing for the
> protein to do all by itself. Proteins change shape all the time. On a
> large scale (forming polymeric forms)... muscle proteins or
> microtubules, yes?
Bob, I thought you said prionologists do not know the mechanism nor
the details of how a PrPres changes a PrPsen into another PrPres. But,
prionologists do know that they must break many covalent amide bonds
(Tony) and about a hundred hydrogen bonds (you, Bob).
Question: do biochemists know exactly what specific bonds need to be
broken and reformed to turn PrPsen into PrPres?
Question: is there a virus/fungus _Injection Syringe Apparatus_ that
specifically cuts into and opens those bonds of PrPsen.
Since Prionologists do not know the mechanism of change of shape/form
of PrP, the easiest explanation, Occam's Razor, suggests that a
virus/fungus Syringe Apparatus is the mechanism that changes
shape/form. Could a virus syringe mechanism become an integral part of
the surface of a PrPsen and change its form/shape into PrPres and this
Syringe become the infectious agent that reshapes and reforms normal
prion proteins?
Archimedes Plutonium
Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> And that a science field should be created whose objective is to
> study the debris of these foreign invaders into the body and to trace
> and catalog what that debris is and how it moves through the body and
> passed out of the body.
I understand that some viruses are icosehedron shaped and that they
have a fancy Syringe type Injection system on their protein coat. This
Syringe apparatus is a long tube and it cuts through the bonds on the
surface of a cell allowing the virus to squirt its RNA into the
cytoplasm.
Now, in prion proteins, they are designed for the cell wall and these
normal prion proteins would be highly susceptable to a Syringe
apparatus whether it is a whole virus particle or whether it is just
the debris of a virus that has come and gone.
I would like to find out the exact biochemical bonds of PrPsen that
must be cut in order for the PrPsen to change form/shape to the PrPres.
If I can find out the exact bonds that must be cut, and if those bonds
match a virus Syringe apparatus specifically designed to open those
precise bonds. Then, I have found the mechanism that turns a PrPsen
into a PrPres. Not only will I have found the mechanism of prion
disease but also what makes prion diseases infective-- a snippet of a
virus/fungus
Bennett
Archimedes...@dartmouth.edu (Archimedes Plutonium) wrote:
> In article <36f1b0ba...@agate.berkeley.edu>
> bbr...@uclink4.berkeley.edu (Bob) writes:
>
> > Don't need a virus etc. This a perfectly reasonable thing for the
> > protein to do all by itself. Proteins change shape all the time. On a
> > large scale (forming polymeric forms)... muscle proteins or
> > microtubules, yes?
>
> Bob, I thought you said prionologists do not know the mechanism nor
> the details of how a PrPres changes a PrPsen into another PrPres. But,
> prionologists do know that they must break many covalent amide bonds
> (Tony) and about a hundred hydrogen bonds (you, Bob).
>
> Question: do biochemists know exactly what specific bonds need to be
> broken and reformed to turn PrPsen into PrPres?
>
They know what amide bonds need to be broken, and since the proposed
structure of PrPres was published a month or so ago they will have a good
idea what H-bond will be broken/reformed.
> Question: is there a virus/fungus _Injection Syringe Apparatus_ that
> specifically cuts into and opens those bonds of PrPsen.
>
Hmmm - the apparatus you're referring to is complex, and has nothing to do
with specific proteolysis, as far as I know.
> Since Prionologists do not know the mechanism of change of shape/form
> of PrP, the easiest explanation, Occam's Razor, suggests that a
> virus/fungus Syringe Apparatus is the mechanism that changes
> shape/form.
I'd have thought that Occams Razor would say that the simplest solution was
that the protein changed due to instrinsic properties of itself - no need for
another factor?
Could a virus syringe mechanism become an integral part of
> the surface of a PrPsen and change its form/shape into PrPres and this
> Syringe become the infectious agent that reshapes and reforms normal
> prion proteins?
If so - it would have been detected LOONNGG ago in infectious prion preps.
Cheers
Bennett
-----------== Posted via Deja News, The Discussion Network ==----------
http://www.dejanews.com/ Search, Read, Discuss, or Start Your Own
James Kibo Parry
Archimedes Plutonium (Archimedes...@dartmouth.edu) replied to himself:
>
> Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> >
> > Also, someone expert on knowing the details of viral sensory
> > receptors and cutting-equipment and someone expert on PrPsen structure
> > would be able to roughly point at a particular family of viruses or
> > fungus whose *sensory equipment* would most easily do the job of
> > reforming PrPsen into PrPres.
>
> is implicated in Alzheimers disease. Now, here is a possible
> unification of Alzheimers to Prion diseases. If the culprit in both
> diseases is a snippet of the virus/fungus/bacteria protein coat and
> even a snippet of the DNA/RNA of the virus/fungus/bacteria.
You know, Arch, your theory that a virus, a fungus, and a bacterium are
the same thing would be even more fun if you worked in a few more things.
Like, you could say "virus = fungus = bacterium = Hostess snack cake =
elastic waistband = bottle rocket = my left sock."
Then you'd get the Nobel Prize for tying together the most unrelated things!
I mean, it takes a GENIUS like Archie to realize that two completely
unrelated things, such as fungi and viri, are exactly the same.
> I believe, although I do not know, and perhaps Tony will quickly come
> to the rescue by saying that there exists such a field of study.
>
> Anyway, I am going to suggest that there exists no hard core field of
> science study of virus, fungus, bacterial debris in the body of the
> host. And that a science field should be created whose objective is to
> study the debris of these foreign invaders into the body and to trace
> and catalog what that debris is and how it moves through the body and
> passed out of the body.
And once all viruses are eradicated, no more pooping! Hooray!
> I suspect there is no such field of science and that the knowledge of
> this subject is kept with the knowledge of those particular viruses or
> fungus that catch our attention. And that many scientists neglect what
> happens to the debris of these foreign invaders of the body. If my
> model of prion disease and Alzheimers is correct, would imply that both
> of these diseases are caused by debris of a foreign invader such as a
> virus.
Um, Arch, the virus only gets out of the cell when the cell pops and is dead.
I suspect that your cells are exploding may be a bigger problem than what
happens to any pieces of the virus after the virus is killed.
> It is usually the case that when a human kills another human it is
> via the arrow or the gun bullet or the missile that the human sends the
> other.
Archie has just proven that people don't kill people, guns kill people!
You're the exact opposite of Ted Nugent! Except that you're not sane.
> Likewise, the nucleic acid of a virus, or fungus or bacteria may
> not kill the host but the debris such as protein coating and coating
> sensory equipment that causes the disease in the host.
>
> If there is not a formal science on this already, what would be a
> good name for the science study of the material shed by a parasite?
> Parasite Byproducts?
And what about parasites that reply to their own articles, and the material
they shed all over the Internet?
-- K.
Mmm, Alpo Parasite By-Products...
Archimedes Plutonium
Bennett <benne...@my-dejanews.com> writes:
> They know what amide bonds need to be broken, and since the proposed
> structure of PrPres was published a month or so ago they will have a good
> idea what H-bond will be broken/reformed.
Does that article detail every bond change from PrPsen to PrPres?
Archimedes Plutonium
can those bonds be posted to the Internet
Archimedes Plutonium
> They know what amide bonds need to be broken, and since the proposed
> structure of PrPres was published a month or so ago they will have a good
> idea what H-bond will be broken/reformed.
>
> > Question: is there a virus/fungus _Injection Syringe Apparatus_ that
> > specifically cuts into and opens those bonds of PrPsen.
> >
>
> Hmmm - the apparatus you're referring to is complex, and has nothing to do
> with specific proteolysis, as far as I know.
Someone wrote that the amide bond was singular, and someone wrote
that this amide bond was covalent. That is a mighty tough bond to break
for a protein interacting with an identical protein save a change of
shape/form. To date, Prusiner has never given a model for the mechanism
of how the PrPres changes PrPsen. Your Proteolysis is not enough to cut
a covalent bond.
But I suspect that a virus injection system on the protein coat of a
virus has the arsenal and equipment to break a covalent amide bond.
Bennett, you remarked that you are familiar with the HIV virus. Can
you please tell me if the HIV has bond breaking equipment on its viral
coating?
Anthony J. Pelletier Ph.D.
Archimedes Plutonium wrote:
>
> Could someone please elaborate for me how easily a virus sensory
> receptors are able to cut-into a protein molecule such as PrPsen and
> once cut into, how easily that viral equipment can then reform and
> reshape the PrPsen molecule into a tightly-wound PrPres.
Never heard of a viral sensory receptor. So, I cannot elaborate. I know
a reasonable amount about viruses, but I have never heard of this.
>
> Also, someone expert on knowing the details of viral sensory
> receptors and cutting-equipment and someone expert on PrPsen structure
> would be able to roughly point at a particular family of viruses or
> fungus whose *sensory equipment* would most easily do the job of
> reforming PrPsen into PrPres.
"Cutting-equipment" makes sense to me. You probably mean proteases.
PrPres, remember, is fairly resistant to these.
As for what is the best canditate for doing the job of converting PrPsen
into PrPres, we've already told you that the experimental evidence shows
the best candidate is PrPres itself, perhaps with a chaperone protein to help.
BTW, You have confused something I tried to tell you. When I was talking
about breaking amide bonds, I was refering to how PrPsen would be
degraded, not how PrPsen would be convereted to PrPres.
-tony
*********************************************************
Anthony J. Pelletier, Ph.D.
Assistant Professor, Department of Cell Biology
The Scripps Research Institute
Mail stop SBR12
10550 North Torrey Pines Rd.
La Jolla, CA 92037
(619) 784-9760
Bennett
It's been a while - I'll try to catch up.
With regards to your question on the article of the PrPres structure - I
haven't read the full text but they will have detailed (if not described)
the structure, and hence intramolecular bonds, of PrPsen vs PrPres. Getting
full-text articles for free is difficult, and I haven't got personal access,
so no, at the moment I can't give you an internet access to them :-(
>
> Someone wrote that the amide bond was singular, and someone wrote
>that this amide bond was covalent. That is a mighty tough bond to break
>for a protein interacting with an identical protein save a change of
>shape/form. To date, Prusiner has never given a model for the mechanism
>of how the PrPres changes PrPsen. Your Proteolysis is not enough to cut
>a covalent bond.
>
Errr, that's exactly what proteolysis is - the cutting of an amide bond.
>
> Bennett, you remarked that you are familiar with the HIV virus. Can
>you please tell me if the HIV has bond breaking equipment on its viral
>coating?
HIV has a protein called gp41 - it unfolds when the virus binds to a cell
and pierces the fatty membrane of the cell (much easier than cutting an
amide bond I should imagine). Not really the same thing at all...
On the other hand HIV does _contain_ a protease enzyme inside it, but that's
almost irrelevant. There are plenty of proteases (of different
specificities) inside normal cells, and I don't think there's much
implication of HIV in prion disease :-p
Cheers
Bennett
Bob
(Archimedes Plutonium) wrote:
>
> Someone wrote that the amide bond was singular, and someone wrote
>that this amide bond was covalent. That is a mighty tough bond to break
>for a protein interacting with an identical protein save a change of
>shape/form. To date, Prusiner has never given a model for the mechanism
>of how the PrPres changes PrPsen. Your Proteolysis is not enough to cut
>a covalent bond.
???
That is the common process carried out by any proteolytic enzyme. That
is what proteases do, break amide (peptide) bonds.
bob
Archimedes Plutonium
"Anthony J. Pelletier Ph.D." <anth...@scripps.edu> writes:
> "Cutting-equipment" makes sense to me. You probably mean proteases.
> PrPres, remember, is fairly resistant to these.
> As for what is the best canditate for doing the job of converting PrPsen
> into PrPres, we've already told you that the experimental evidence shows
> the best candidate is PrPres itself, perhaps with a chaperone protein to help.
> BTW, You have confused something I tried to tell you. When I was talking
> about breaking amide bonds, I was refering to how PrPsen would be
> degraded, not how PrPsen would be convereted to PrPres.
The Prusiner camp continues to talk about "chaperone". They are
embarrassed that a virus or fungus is the cause of prion diseases and
so they continue to hide behind a polite diversionary term of
"chaperone". And they even slip in the adjective of protein for protein
chaperone.
The Prusiner camp did a anti-science campaign of telling biologists
"either you find a virus that causes prion disease or my theory of
protein-only is correct". This campaign was a disservice to science for
it was never a "Deciding Experiment".
Here is a Deciding Experiment: (1) Since it is claimed that prion
diseases are hereditary, then create a hereditary prion disease from
the egg+sperm onwards. Our genetic engineering is good enough to cut
and splice the gene that gives cause to PrPres. So, genetically
engineer a mouse or hamster whose gene sequence will yield the PrPres
from the moment of egg+sperm onwards. Such a controlled experiment will
verify that no foreign DNA/RNA caused the PrPres.
Such an experiment is foreign DNA/RNA free
(2) Then, transfer that PrPres if it can be done, into a egg+sperm
union and see if this egg+sperm+PrPres also yields prion disease.
I would guess that (1) cannot be accomplished simply because PrPres
requires an element of a virus or fungus, not just the bodies own gene
manipulation.
Bennett
Archimedes...@dartmouth.edu (Archimedes Plutonium) wrote:
>
> The Prusiner camp continues to talk about "chaperone". They are
> embarrassed that a virus or fungus is the cause of prion diseases and
> so they continue to hide behind a polite diversionary term of
> "chaperone". And they even slip in the adjective of protein for protein
> chaperone.
They're still relying on the strong evidence against any DNA/RNA-based
lifeform being part of the prion process of PrP structural change. The
polite term chaperone is not polite, its an actual term of the trade and was
in use long before prions were looked into.
>
> Here is a Deciding Experiment: (1) Since it is claimed that prion
> diseases are hereditary, then create a hereditary prion disease from
> the egg+sperm onwards. Our genetic engineering is good enough to cut
> and splice the gene that gives cause to PrPres. So, genetically
> engineer a mouse or hamster whose gene sequence will yield the PrPres
> from the moment of egg+sperm onwards. Such a controlled experiment will
> verify that no foreign DNA/RNA caused the PrPres.
>
Well, depends if that can be done. It appears that the PrP gene is translated
into PrPsen, in all the sequences known so far. The alteration to PrPres
happens later, randomly. This can be enhanced by certain factors, of which
PrPres itself is thought to be one - necessary, but not sufficient maybe.
The zygote experiment you outline might well not work because of the time
required for a random change in PrPsen to occur. A better idea might be an
in-vitro protein translation system (I think they exist these days). You'd
make more of the protein, and more quickly than in a cell-based system. The
alternative is a transfection of a cell, either mammalian or bacterial, with
the gene, but that's fraught with potential problems, especially if we're
concerned with how the thing folds up.
Anyway, as I said before, just because a disease is hereditary doesn't mean
that the disease process starts immediately.
Anthony J. Pelletier Ph.D.
Archimedes Plutonium wrote:
>
>
> Here is a Deciding Experiment: (1) Since it is claimed that prion
> diseases are hereditary, then create a hereditary prion disease from
> the egg+sperm onwards. Our genetic engineering is good enough to cut
> and splice the gene that gives cause to PrPres. So, genetically
> engineer a mouse or hamster whose gene sequence will yield the PrPres
> from the moment of egg+sperm onwards. Such a controlled experiment will
> verify that no foreign DNA/RNA caused the PrPres.
>
> Such an experiment is foreign DNA/RNA free
>
Been done. (in animal models...obviously not in humans)
Read the literature.
I've no time for you if you cannot be bothered to see what has been done.
Archimedes Plutonium
it relate to the concept of autoimmune?
Bennett, would the bacterial protein that mimics as described below
re: chlamydia, would it be
classified as a chaperone in the below chlamydia article.
It seems as though Chlamydia is cropping up all over the places these
days. Awhile ago it was the implicated culprit in Alzheimers and now it
is implicated in heart attacks, not to forget its known disease of
pneumonia
--- quoting in parts SCIENCE NEWS, 13MAR99 ---
Chlamydia protein mimics heart muscle
An attempt to unravel how certain viral infections harm the heart may
have produced an explanation for the tantalizing link between some
bacteria and the development of heart disease. What researchers have
stumbled upon is in essence a dangerous case of mistaken identity.
... have been studying how infections by members of the coxsackie
virus family stimulate an animal's immune system to attack its heart.
The researchers found that injections of a small fragment of the
heart-muscle protein myosin generated heart damage nearly identical to
that caused by the viruses. They therefore wondered whether the viruses
have proteins structurally similar to the myosin fragment. Such
molecular mimicry could explain why the immune system responds to the
microbes by attacking the heart.
Yet when Penninger's team searched a database of viral and bacterial
proteins, the only match to the myosin fragment was part of a surface
molecule made by the bacterium Chlamydia trachomatis. That match
intrigued Penninger because another member of the chlamydia family,
Chlamydia pneumoniae, has been associated with heart disease (SN:
6/14/97, p. 375). A recent study even suggested that antibiotics might
prevent the development of heart attacks ...
Penninger found that C. pneumoniae has a surface molecule identical
to the one in C. trachomatis that mimics myosin. He and his colleagues
even showed that injections of this bacterial protein have a dramatic
effect. "We can take a piece of the bacteria, put it into [mice], and
give them heart disease," says Penninger. He argues that his group has
offered the first proof of a mechanism by which chlamydia bacteria may
trigger heart problems.
Epidemiology studies, however, have linked the bacteria to
atherosclerosis, a thickening of blood vessel walls, not to a direct
immune attack on the heart, ..."...speculation about what the mechanism
might be,"
--- end quoting in parts SCIENCE NEWS, 13MAR99 ---
In article <7dad8a$nj8$1...@nnrp1.dejanews.com>
Bennett <benne...@my-dejanews.com> writes:
> They're still relying on the strong evidence against any DNA/RNA-based
> lifeform being part of the prion process of PrP structural change. The
> polite term chaperone is not polite, its an actual term of the trade and was
> in use long before prions were looked into.
>
Archimedes Plutonium
"Anthony J. Pelletier Ph.D." <anth...@scripps.edu> writes:
> Been done. (in animal models...obviously not in humans)
> Read the literature.
>
I think you are a tad confused about my experiment for it has the
*PrPres as an actual gene* producing the protein PrPres. Bennett seems
to be saying that there has never been such an experiment either.
> I've no time for you if you cannot be bothered to see what has been done.
Well, actually I am now going to devote more time to the literature,
only not the literature that may seemingly help you, but instead that
helps my cause. The below article points out many interesting aspects
of protein coatings for which I believe a large science field of
diseases should be started. I believe the prion and Alzheimers and
Parkinsons are a new disease class, only not what the Prusiner model
assumes. Rather instead, the mechanism behind these three diseases is a
virus, fungus, or bacteria protein coating debris. Prusiner may incite
"chaperone". Perhaps a more clearer picture is that the protein debris
causes an autoimmune response such that it glues, molecularly glues a
PrPsen into a PrPres. Or in the case of Alzheimers, some chlamydia
pneumonia bacteria protein debris causes an autoimmune response to glue
together the neurofibrillary tubes into tangles.
I do not know about Parkinsons, as of yet, for I know almost nothing
about it. Can someone summarize Parkinsons disease?
--- quoting in parts SCIENCE NEWS 20FEB99 ---
Enzyme erases DNA's molecular coating
For reasons that still perplex scientists, clusters of atoms called
methyl groups blanket much of the DNA in humans and other vertebrates.
Several years ago, investigators uncovered enzymes that could attach
these methyl groups to DNA, a process known as methylation. Now, a
Canadian research group reports identifying a demethylase, an enzyme
able to strip those methyl groups from DNA.
The discovery has attracted considerable attention because shifting
patterns in methylation seem to regulate the activity of genes,
particularly during the growth of embryos. Furthermore, the genomes of
cancer cells exhibit abnormal methylation, an anomaly that may fuel the
runaway growth of the cells.
... reasoned that any demethylating enzyme would contain an amino
acid sequence capable of binding methylated DNA. By scanning a database
for gene fragments encoding such a sequence, the researchers identified
several candidate human demethylase genes.
As hoped, the protein encoded by one of those genes proved able in
test-tube experiments to detach methyl groups from DNA. Moreover, when
the gene was slipped into cells, demethylation occurred in several
stretches of DNA, the team reports in the Feb. 18 NATURE.
"We have shown by a number of different assays that [the DNA] gets
demethylated,".. Additional experiments by his group suggest that the
enzyme produces a reaction between methylated DNA and water that
results in unmethylated DNA and methanol.
Several other research groups have reported discovering enzymes with
demethylation activity, but the claims haven't proved compelling to
many scientists. The latest announcement has also drawn some
skepticism.
" They have to have genetic evidence that this [enzyme] is involved
in reshaping methylating patterns,"... To do that, ...should create
mice that have a mutation in the gene for the putative demethylase and
observe whether that mutation alters methylation in the animal.
"Is it involved in generating methylation patterns in real life?... "
.. who has started to generate mice lacking the enzyme.
The researchers have some evidence suggesting that the protein plays
a role in cancer. Its gene is active in tumor cells. When the
scientists used so-called antisense technology (SN: 8/6/94, p. 88) to
thwart the gene's activity, they produced a dramatic result. "If you
knock [the gene] out, cancer cells don't grow anymore,"...
Enzyme erases DNA's molecular coating
A newly discovered enzyme strips DNA of clusters of atoms called
methyl groups÷a function implicated in the regulation of gene activity.
References: Bhattacharya, S.K. . . . M. Szyf. 1999. A mammalian
protein with specific demethylase activity for mCpG DNA. Nature
397(Feb. 18):579.
--- end quoting in parts SCIENCE NEWS 20FEB99 ---
Archimedes Plutonium
Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> Rather instead, the mechanism behind these three diseases is a
> virus, fungus, or bacteria protein coating debris. Prusiner may incite
> "chaperone". Perhaps a more clearer picture is that the protein debris
> causes an autoimmune response such that it glues, molecularly glues a
> PrPsen into a PrPres. Or in the case of Alzheimers, some chlamydia
> pneumonia bacteria protein debris causes an autoimmune response to glue
> together the neurofibrillary tubes into tangles.
If the above is roughly correct, would make integral sense. I say
integral because it is nice to be able to tie together two or three
diseases all into one nice concise picture. You have a virus or fungus
or bacteria protein coating snippet or coating weapon system. This
coating snippet causes the autoimmune system to engage. What happens is
that in prion disease the autoimmune system causes a protein like glue
substance, a molecular glue to tightly wind the PrPsen into PrPres. In
Alzheimers, the Chlamydia pneumonia bacteria also discards its protein
coating and the autoimmune system sends out another response only this
time, instead of a molecular glue for PrPsen, in Alzheimers, it is a
molecular glue of the neurofibrillary tubes.
Since I do not know the Summary of Parkinsons disease, I cannot speak
about some glue on something. Perhaps someone can help me with a
Parkinsons disease summary.
I know of alot of proteins that are excellent glues. I use the term
glue in a broad sense. Actually all glue or sticky substances are
really the electromagnetic force in atomic/molecular bonding. But the
word "glue" is a nice quick term.
Perhaps, these three diseases, they are all three protein diseases,
and they seem to accumulate protein junk. So a glue caused by the
autoimmune system which was caused by a foreign DNA/RNA of its
discarded protein coat/equipment. It would be nice to say those three
diseases all follow in that model.
anthonyp...@my-dejanews.com
Archimedes...@dartmouth.edu (Archimedes Plutonium) wrote:
> In article <36F90686...@scripps.edu>
> > Read the literature.
> >
>
> I think you are a tad confused about my experiment for it has the
> *PrPres as an actual gene* producing the protein PrPres. Bennett seems
> to be saying that there has never been such an experiment either.
>
Yes. I was confused because I thought you were proposing a new experiment.
Upon re-reading it, I realized that you were proposing the same stupid idea
we had already tried to explain to you. What has been done is show that a
mutation introduced into the gene will result in prion disease. There are two
things wrong with your idea: 1: it is not a requirement of a genetic disorder
that it manifest itself from the moment of conception. For example,
Huntington's Chorea is clearly genetic and the first symptoms do not appear
until midlife. In fact, I would venture that most non-lethal genetic diseases
do not become symptomatic until well after birth. So, the experiment you
proposed was silly from the standpoint that it had nothing to do with the
definition of genetic disorder. 2: Your experiment is even sillier because it
is driven by the assumption that the sperm/egg are free of viruses.
Presumably, you think that this would allow you to test whether some
subsequent exposure to a virus or such was the cause of the disease. There
are a number of logical flaws in this, however, I will stick to the factual
flaws. The assumption that the sperm and egg are necessarily free of viruses
is false. there are endogenous viruses that become productive during
development, and there is always the possibility of infectio in the womb
> Well, actually I am now going to devote more time to the literature,
> only not the literature that may seemingly help you, but instead that
> helps my cause. The below article points out many interesting aspects
> of protein coatings for which I believe a large science field of
> diseases should be started.
The study of gene regulation by methylation is nothing new.
But, I applaud your desire to learn more.
Bennett
>In article <36F90686...@scripps.edu>
>> Read the literature.
>>
>
> I think you are a tad confused about my experiment for it has the
>*PrPres as an actual gene* producing the protein PrPres. Bennett seems
>to be saying that there has never been such an experiment either.
>
Well, we can produce PrP from a gene easily enough, but as far as I know it
doesn't default to PrPres, but instead PrPsen (which is later converted).
Cheers
Bennett
Bennett
> Bennett, what is the scientific definition of chaperone, and how does
>it relate to the concept of autoimmune?
A chaperone would be any protein which binds to another and aids its
physiological function in some way. That's a pretty wide definition - one
good example is in the MCH antigen presentation complexes. They tend to
fall apart if they haven't got antigen bound to them, so while they are
being produced a chaperone holds them together.
>
> Bennett, would the bacterial protein that mimics as described below
>re: chlamydia, would it be
>classified as a chaperone in the below chlamydia article.
>
No, not really. They use the word "mimick", which would be best.
Cheers
Bennett
Bob
This is not in reply to anything in particular...
Science 283:1935, March 19, 99, by Jackson et al... Reversible
conversion of human monomeric human prion protein between native and
fibrilogenic conformations.
They use a form of human prion protein made in E. coli, and do in
vitro work with it, showing some interesting changes, some
reversible.
Good discussion, too.
the problem with any such work is trying to decide what is really
relevant to the natural disease, but these are certainly interesting
conversions.
If someone already posted this, my apologies.
bob
Archimedes Plutonium
"Bennett" <nj...@spam.ac.uk> writes:
>
> Well, we can produce PrP from a gene easily enough, but as far as I know it
> doesn't default to PrPres, but instead PrPsen (which is later converted).
I believe for the protein-only theory of Prusiner to be true, then an
infectious PrPres must be produced from the gene-only. Protein-only
implies gene-only.
If unable to produce the infectious PrPres from a gene-only, then the
implication is that infectious PrPres only exists after a
virus/fungus/bacteria modification of PrP. Thus, the chaperone is a
virus/fungus/bacteria molecule or autoimmune induced
virus/fungus/bacteria
Archimedes Plutonium
anthonyp...@my-dejanews.com writes:
> Your experiment is even sillier because it
> is driven by the assumption that the sperm/egg are free of viruses.
> Presumably, you think that this would allow you to test whether some
> subsequent exposure to a virus or such was the cause of the disease. There
> are a number of logical flaws in this, however, I will stick to the factual
> flaws. The assumption that the sperm and egg are necessarily free of viruses
> is false. there are endogenous viruses that become productive during
> development, and there is always the possibility of infectio in the womb
I understand that test tube mice are commonplace, such that they can
be isolated, almost 100% virus free.
The importance of the above experiment are two issues (1) a
protein-only theory implies that a gene that produces PrPres, not the
good PrP of PrPsen, but the bad protein, produces it genetically,
right-off-the-bat so to speak. If Prion diseases are truly protein-only
and also hereditary, then genetics-only can produce a gene that makes
the PrPres genetically.
And the second issue (2) egg+sperm genetic development of bad PrPres
would be proof that the protein-only theory is correct. Because if you
can get a gene to produce or manufacture infectious PrPres is proof
that no virus/fungus/bacteria or autoimmune or chaperone is needed.
So, to prove the Prusiner protein-only theory, provide a gene that
manufactures the infectious PrPres. If you cannot do that, then the
theory needs correcting.
Archimedes Plutonium
bbr...@uclink4.berkeley.edu (Bob) writes:
> the problem with any such work is trying to decide what is really
> relevant to the natural disease
--- quoting in parts SCIENCE, 19MAR1999: 1935-1937 ---
Reversible Conversion of Monomeric Human Prion Protein Between Native
and Fibrilogenic Conformations
G. S. Jackson, L. L. P. Hosszu, A. Power, A. F. Hill, J. Kenney, H.
Saibil, C. J. Craven, J. P. Waltho, A. R. Clarke, and J. Collinge
Prion propagation involves the conversion of cellular prion protein
(PrP^C) into a disease-specific isomer, PrP^Sc, shifting from a
predominantly alpha-helical to a beta-sheet structure. Here, conditions
were established in which recombinant human PrP could switch between
the
native alpha conformation, characteristic of PrP^C, and a compact,
highly soluble, monomeric form rich in beta structure. The soluble beta
form (beta-PrP) exhibited partial resistance to proteinase K digestion,
characteristic of PrP^Sc, and was a direct precursor of fibrillar
structures closely similar to those isolated from diseased brains. The
conversion of PrP^C to beta-PrP in suitable cellular compartments, and
its subsequent stabilization by intermolecular association, provide a
molecular mechanism for prion propagation.
Prion diseases are associated with the accumulation of a
conformational
isomer (PrP^Sc) of host-derived prion protein (PrP^C) with an increase
in its beta-sheet secondary structure content and the acquisition of
partial resistance to digestion with proteinase K (PK). According to
the
protein-only hypothesis, PrP^Sc is the principal or sole component of
transmissible prions. Although the structure of PrP^C has been
determined, the insolubility of PrP^Sc, which is isolated from tissue
in
a highly aggregated state, has precluded high-resolution structural
analysis.
... The precise subcellular localization of PrP^Sc propagation remains
controversial, although considerable evidence implicates late
endosome-like organelles or lysosomes. This alpha-PrP to beta-PrP
conversion, caused by reduction and mild acidification, may be relevant
to the conditions that PrP^C would encounter within the cell after its
internalization during recycling. Reduction and acidification within
the
endosomal pathway is required for activation of diphtheria toxin. Such
a
mechanism could account for the transmitted, sporadic, and inherited
etiologies of prion disease.
--- end quoting in parts SCIENCE, 19MAR1999: 1935-1937 ---
The above mentions diphtheria toxin. That is a bacteria. I wonder
whether it has more connections with prion disease?
I am confused, perhaps it is only a terminology confusion. But the
bad PrP is supposed to be compact such that the protease machinery
cannot cut it down. Yet the bad PrP has beta sheets not alpha helicals.
It would seem to me that beta sheets would provide less compactness
than alpha helicals.
Bob, does a beta sheet have more atoms than a alpha helical?
Bob, could you please tell us the typical size of PrP, compared to a
virus, and how many atoms are we talking about? And a comparison of the
PrP to the Alzheimers neurofibrillary tube.
Archimedes Plutonium
Archimedes...@dartmouth.edu (Archimedes Plutonium) writes:
> So, to prove the Prusiner protein-only theory, provide a gene that
> manufactures the infectious PrPres. If you cannot do that, then the
> theory needs correcting.
(1) Yes, sir, I do believe that the Prusiner protein-only theory
implies that a gene-only can manufacture the infectious PrPres. That a
human gene can be manipulated into producing infectious PrPres. And if
this PrPres is injected into a healthy individual, he/she will become a
diseased person.
(2) However, a Prusiner protein-only theory with required chaperone
does not imply a gene-only can manufacture the infectious PrPres.
Assume the chaperone is another protein so as to keep the integrity of
the protein-only theory. Of course, if the chaperone is a
virus/fungus/bacteria induced particle, then the protein-only theory is
a fake theory.
So, which accords more with experiments, 1 or 2? Well, since there
has never been a case of a fetal death due to PrPres, and since never
there was a young individual case of prion disease, it is safe to say
that 1 is false and that Prion Disease necessarily requires a
chaperone. The requirement of a chaperone also affords an explanation
for the bizarre characteristic of both hereditary simultaneously
infectious. If it were protein-only without any chaperone, then the
logic of hereditary simultaneously infectious is inconsistent. But when
2 variables are at work -- PrP and chaperone, then these 2 variables
allow for a mixing of heredity along with infectivity.
So, what I need now is a deciding experiment as to whether the
chaperone is another protein or whether the chaperone is a
virus/bacteria/fungus particle. Here we will say that if it is an
autoimmune response to a virus/bacteria/fungus, regardless of whether
the autoimmune response is another protein or not, that the autoimmune
response is caused by a virus/bacteria/fungus.
Now, is there anything in the experiments or observations to date
that could support whether the chaperone is protein or
virus/bacteria/fungus?
I believe there is and it follows the same science investigation of
the fetal and young prion disease.
Alzheimers is related to Prion disease. There has never been a case
of fetal prion disease or young individual or gene-only PrPres.
So, we ask the very same question about Alzheimers disease, assuming
that it is intricately related to Prion disease. Has there ever been a
gene-only Alzheimers disease, that is, a fetal birth of Alzheimers or a
young individual stricken with Alzheimers. And further yet, can we make
and manipulate a gene to produce Alzheimers disease? The answer to all
of these is again no, the same no as in prion disease. So, both prion
and Alzheimers are old individuals diseases.
However, in Alzheimers there is associated Chlamydia pneumonia
bacteria. The evidence of this Chlamydia in all cases of Alzheimers is
strong evidence. Thus, Chlamydia bacteria is implicated as the
chaperone in Alzheimers disease. The Neurofibrillary tubes would be the
PrP of Alzheimers disease and the chaperone is a autoimmune response to
Chlamydia bacterial particles.
Archimedes Plutonium
> Chlamydia bacteria is implicated as the
> chaperone in Alzheimers disease. The Neurofibrillary tubes would be the
> PrP of Alzheimers disease and the chaperone is a autoimmune response to
> Chlamydia bacterial particles.
I needed to find out much more about Chlamydia, especially to see if
this one class of organisms could be the causitive agent for the 3
encephalopathologies of prion, Alzheimers, Parkinsons. They certainly
are widespread enough. And in the case of one, Chlamydia psittaci,
birds could transport them everywhere. Curiosity: does prion disease
occur more often with bird owners? And sheep and cattle would eat bird
droppings along with their grass. A long time ago, under the impression
that fungus caused prion disease, I asked whether prion disease ever
showed up in desert or dry climates other than in wet jungles for kuru
or wet England. I know of no cattle or sheep in dry climates with
mad-cow or scrapie. But now under the impression of Chlamydia psittaci
with bird spreading perhaps there is some connection?
And it is known that in prion, Alzheimers that no virus was ever
found. But if Chlamydia causes prion and Alzheimers, the Chlamydia can
long disappear when the first symptoms of the disease show up.
--- quoting in part McGraw-Hill Encyc. Sci & Tech, 1997 ---
Chlamydia
A unique genus of bacteria with a growth cycle differing from those
of
all other microorganisms: Chlamydia grow only in living cells and
cannot
be cultured on artificial media. Although capable of synthesizing
macromolecules, they have no system for generating energy; the host
cell's energy system fuels the chlamydial metabolic processes.
Infectious particle. The chlamydial infectious particle, called the
elementary body, is round and small (about 350-450 nanometers in
diameter). It enters a susceptible host cell and changes to a
metabolically active and larger (approximately 800-1000 nm in diameter)
reticulate body that divides by binary fission. The entire growth cycle
occurs within a vacuole that segregates the Chlamydia from the
cytoplasm
of the host cell. The reticulate bodies change back to elementary
bodies, and then the cell lyses and the infectious particles are
released. The growth cycle takes about 48h.
Chlamydial diseases. Diseases are caused by three species of
Chlamydia. Chlamydia trachomatis, occurring in humans, ... contain
glycogen. Chlamydia psittaci, occurring in birds, lower
animals, and humans, ... The TWAR strains have been given their own
species
category, C. pneumoniae. The TWAR elementary body is pear shaped rather
than round, and there is little deoxyribonucleic acid (DNA)
relatedness.
Chlamydia trachomatis. Chlamydia trachomatis is almost exclusively a
human pathogen, and one of the most common. Those strains infecting
humans have no known animal reservoir. Infections occur in two distinct
epidemiologic patterns. In many developing countries, C. trachomatis
causes trachoma, a chronic follicular keratoconjunctivitis. It is the
world's leading cause of preventable blindness, affecting approximately
500 million people, with millions losing their sight. In areas where
this condition is highly endemic, virtually the entire population is
infected within the first few years of life. Most active infections are
found in childhood.
Scarring can develop as a result of severe inflammation of the
conjunctiva. Over a period of years, the scars shrink and distort the
upper eyelid, causing an in-turning of the eyelashes which damages the
cornea and causes blindness. By age 60, more than 20% of a population
can be blinded as a result of trachoma.
Chlamydia trachomatis can be spread sexually. In the United States,
it
is the most common sexually transmitted bacterial pathogen; an
estimated 4.5 million cases occur each year. The most common
manifestation of this infection is nongonococcal urethritis in males.
The cervix is the most commonly infected site in women. Ascending
infections can occur in either sex, resulting in epididymitis in males
or endometritis and salpingitis in females. Chlamydial infection of the
fallopian tube can cause late consequences such as infertility and
ectopic pregnancy, even though the earlier infection is asymptomatic.
For
some women, their first knowledge of having had a chlamydial infection
occurs when they are being evaluated for infertility or are
hospitalized
with an ectopic pregnancy. Thus chlamydial infection in the female can
be particularly insidious and dangerous.
The infant passing through the infected birth canal can acquire the
infection and may develop either conjunctivitis (called inclusion
conjunctivitis of the newborn, or inclusion blennorrhea) or pneumonia.
In the United States, C. trachomatis is the leading cause of
conjunctivitis in the first month of life, and of pneumonia in the
first
6 months.
All of the diseases mentioned above involve mucous membranes. There
is a more invasive form of C. trachomatis that causes a systemic
sexually transmitted disease called lymphogranuloma venereum.
Lymphogranuloma venereum has a worldwide distribution, although it is
more common in some tropical countries. This disease has a predilection
for lymphoid tissue involvement. It occurs in stages: the primary stage
involves small, superficial, usually painless genital lesions; in the
secondary stage, inguinal buboes (infected lymph nodes) are the common
finding. If untreated, the disease may progress to stages involving
widespread tissue destruction of genital and intestinal tracts.
Chlamydia psittaci. ... as a cause of abortion in
sheep, cattle, and goats. ... Chlamydia psittaci can
infect humans, causing the disease psittacosis. Psittacosis can occur
as
pneumonia or a febrile toxic disease without respiratory symptoms.
...
Chlamydia pneumoniae (TWAR). Chlamydia pneumoniae appears to be a
human pathogen with no animal reservoir. It is of worldwide
distribution
and may be the most common human chlamydial infection. It appears to be
an important cause of respiratory disease, being found in association
with sporadic cases of community-acquired pneumonia and epidemics of
mild pneumonia. In addition, C. pneumoniae infection has been linked to
coronary artery disease.
...
--- end quoting in part McGraw-Hill Encyc. Sci & Tech, 1997 ---
Anthony J. Pelletier Ph.D.
Archimedes Plutonium wrote:
>
> I understand that test tube mice are commonplace, such that they can
> be isolated, almost 100% virus free.
>
Yes, but "almost" is not 100%, as we have discussed. As far as I know,
there are not strains of mice that lack the endogenous retroviruses.
> [...]. If Prion diseases are truly protein-only
> and also hereditary, then genetics-only can produce a gene that makes
> the PrPres genetically.
this is false. There is no reason to assume this and it is not a
prediction of the model.
>
> And the second issue (2) egg+sperm genetic development of bad PrPres
> would be proof that the protein-only theory is correct. Because if you
> can get a gene to produce or manufacture infectious PrPres is proof
> that no virus/fungus/bacteria or autoimmune or chaperone is needed.
>
As I said, the virus/fungus/bacteria question is probably not well
addressed (well, virus anyway) by making it happen in the embryo.
As for chaperone, there are no cells devoid of all chaperones. They are
essential for cellular function and an integral part of the cell.
> So, to prove the Prusiner protein-only theory, provide a gene that
> manufactures the infectious PrPres. If you cannot do that, then the
> theory needs correcting.
As has been pointed out, a gene that manufactures infectious PrPres
probably has been proved.
As for your requirement that it do so without first making the PrPsen
and then converting it to PrPres, that is irrelevent.
As the paper you recently quoted pointed out, the conversion may take
place in the endosome or lysosome, which no normal protein would see
until it was ready for degradation. The cute twist in all of this that
you are missing is that the normal protein may work perfectly well until
it is sent to the compartment in which it is to be degraded (I myself
have favored it happening in the compartment where the proteins are
made...but, the recent evidence may make me re-evaluate that). There,
the pH changes (these compartments are quite acidic) and other solvent
changes may favor the conversion to the dangerous, and protease
resistent forms. This trick has also been exploited by a number of
viruses and bacteria. Kind of a Trojan Horse trick.
--
Archimedes Plutonium
"Anthony J. Pelletier Ph.D." <anth...@scripps.edu> writes:
> There,
> the pH changes (these compartments are quite acidic) and other solvent
> changes may favor the conversion to the dangerous, and protease
> resistent forms. This trick has also been exploited by a number of
> viruses and bacteria. Kind of a Trojan Horse trick.
What viruses and bacteria? Possibly the Chlamydia bacteria? What is
the name of these compartments?