Solving Alzheimers, Huntington, Prion diseases; Files150 and 151 of www.iw.net/~a_plutonium



"Archimedes Plutonium" <[email protected]> wrote in message
news:[email protected]...
> "Wyrin" <[email protected]> wrote in message
news:<[email protected]>...
> > "Archimedes Plutonium" <[email protected]> wrote
> > in message
> > news:[email protected]...
> > > "Wyrin" <[email protected]> wrote in message
> > news:<[email protected]>...
> > >
> > > >
> > > > I've tried this before but... AP, try looking at
> > > > Pathologic conformations of prion proteins. (1998)
> > > > Annu Rev Biochem
67
> > > > p793-819 Also, I like to look at the serpin analogy
> > > > http://eagle.mmid.med.ualberta.ca/publications/JMB2-
> > > > 93p449.pdf
> > > >
> > > > AP, do you claim that crystallisation is
> > > > thermodynamically
impossible?
> > > >
> > > > Amyloid is just a great big Conga line of drunk
> > > > proteins at a New
years
> > > > party, and the normal proteins just aint drunk
> > > > enough to join in...
yet.
> > > > Until it hits midnight... An I know its not
> > > > thermodynamically impossible to get drunk. Trust
me
> > >
> >
> > > Sorry if it sounds like I am picking on you Wyrin, but
> > > you deserve it with your scatterbrained tidbits above.
> >
> > It didnt sound like you were picking on me - just that
> > you were spouting
a
> > diatribe with little basis in fact. Those scatterbrained
> > titbits - IF YOU ACTUALLY BOTHRERED TO READ THEM - would
> > answer some of your questions
>
> some files I cannot access for it interfers with my
> killfile such as pdf

convenient. So, you cant actually use any scientific
literature to back up your arguments?

> >
> > > Crystallization is thermodynamically possible, and you
> > > know what Wyrin, thousands perhaps millions of
> > > chemists and their students have worked out enthalpies
> > > and entropies and whether the reaction will go and the
> > > rates of reaction. But why is it Wyrin that no-one
> > > ever worked out whether bad-prions react and change
> > > good prions. Is it because Mr. Prusiner is unable to
> > > do any such calculations? So why have you Wyrin not
> > > given any website that shows the entropy and
> > > enthalpies for prion reactions? Is it because they are
> > > nonexistant?
> >
> > If you looked at the first reference I gave you, you
> > would find some of
the
> > answer to this Pathologic conformations of prion
> > proteins. (1998) Annu Rev Biochem 67 p793-819
> >
http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev-
.biochem.67.1.793
> > Go to a local library and ask for this article, or
> > purchase it online
> >
>
> If you were scientifically objective about prion disease
> then you would not be in these newsgroups with the
> attitude of saying "you are wrong and here, I deposit for
> you sites in which to correct your misconceptions"

That is exactly what a scientist does. Uses the evidence to
point out misconceptions and put forward a different
argument/theory. Dont expect you to understand this

>Your trouble Wyrin is that you take some lofty high ground
>that you are the authority on prions and that you are here
>to correct everyone else. When you fact you are an
>incompetent in Prion science.

:cool: Soon to have a PhD to back me up (if all goes to plan)

> > What do you think of the existance of prions in yeast?
> >
> If you had a gram of science objectivity, Wyrin, you would
> thence realize that since yeast which is chock full of
> prion proteins yet is utter harmless to animals, would
> indicate strongly that the Prusiner Model for prions is
> false. Why should prions in yeast never act like prions in
> animals, unless of course the Prusiner Model is a fake
> science model. But you, Wyrin, just does not have the
> science objectivity.

Why do some viruses harm some animals and not others? Yeast
prions have little homology to animal prions and there is
no reason why they would be expected to cause prion disease
in animals

> > > Would you say Wyrin that the chances of any scientist
> > > finding a correct model for a disease wherein that
> > > scientist has little to no clue as to what the
> > > function or role of their main-element or main
> > > molecule of the disease (in this case normal-prions).
> > > Would you say that the chances of the Model being
> > > wrong is something about 99% with maybe a 1% chance
> > > that the Model is correct? Because that is where I
> > > would place the numbers.
> >
> > What is the probability of correctness of the opinion of
> > a person who is
so
> > inherently biased against Prusiner?
>
> No, I am both biased against Prusiner but also _able_ to
> be biased for Prusiner. But you, Wyrin, is incapable of
> being biased against Prusiner. Perhaps it is because you
> are part of the establishment with your job and career at
> stake. This is a common problem with most scientists in
> that they know a science theory is wrong but they cannot
> speak out against it because of their biweekly paycheck.

Currently unemployed awaiting my PhD viva - I wish i had
that paycheck! I dont understand why you have to use
personal attacks on my values and employment instead of
science. Apart from your history of doing that. Scientists
will go along with popular ideas to get funding for
research, but thats a different issue entirely

> > He proposed a dogma-breaking theory and got a nobel
> > prize for it. Ok, it might have been earlier than he
> > deserved, but that doesnt invalidate the growing body of
> > evidence that has been compiled to sugest his theory
could
> > be true
> >
>
> There is no growing body of evidence in support of
> Prusiner. There is evidence of variant types of bad prion
> proteins which disproves the Prusiner Model. How can that
> Model reconcile over 13 type flavors of bad prion proteins
> just for cows. And the growing evidence that a protein
> scissors is the cause of prion accumulation. That the
> scissors creates the bad prions. And the growing evidence
> that Alzheimers is very much like Prion disease and no-one
> expects the Prusiner Model to work for Alzheimers.

None of these are mutuallty exclusive. I would insert a few
referneces that duiscuss that here, but you seem to reject
anything I put forward as evidence. It has been shown that
the efficiecy of prion conversion is determined in part by
the degree of homology between PrPSc and PrPC - that can
account for some strain variation. Glycoform and
conformational issues also have an effect

> Wyrin, I said the probability is that of 99% wrong for
> the model and perhaps a low 1% that Mr. Prusiner
> guessed it correctly. For it would have to be a guess
> when a scientist constructs a Model around a disease
> but has little to no understanding of the protein
> function of prions.

A good scientist would know that those values you put on it
have no meaning - thats why i gave no response. Do I think
Prusinerr has the whole story - no, and thats what I have
spent the past 3 years looking at. Do I think that a protien
can be infectious under prusiner's prion concept? yes. The
prion theory is not as clear cut as you make out, and there
is much scope within it for different models. Do I think
much more work needs to be done before we know the whole
story? Yes. That doesnt mean that we can put forward
theories based on the evidence at hand.

> So, Wyrin, please answer my question: what is the
> likelihood that the Prusiner Model is correct when it was
> constructed without knowing or understanding of what a
> prion protein functions as within the body. I said the
> probability was 99% wrong and only a 1% chance that Mr.
> Prusiner had guessed it correctly.

I cannot answer this with values that mean anything. All i
can say is that our understanding will be enhanced greatly
by working out what PrP does. Until then, we can still put
forward based on the evidence at hand

> Tell me, did anyone ever think that Alzheimers was a virus
> led disease? Or that Parkinsons was a virus led disease?
> That is old history.

Not really, because they werent seen to be
transmissible diseases.

> It is scissors that is the cause of Prion disease as it is
> scissors that is the cause of Alzheimers and Parkinsons.
> It maybe metal-ions such as magnetic manganese that
> corrupts the prion-scissors and that when meat is eaten
> from infected prion those prion-scissors or magnetic-
> manganese get lodged into the new victims brains.

So go and claim your nobel prize. I personally think metal
ion binding might have a lot to do with the switch from PrPC
to PrPSc, but as for the underlying reason behind that, its
not clear. Its the upstream factors i believe to be
interesting. The fact you use the term prion - meaning an
infectious protein - is confusing given your aversion to the
prusiner theories. And the model you suggest isnt
necessarily that different

> The Prusiner Model is equivalent to saying that the world
> has a supercatalyst. Platinum is a normal catalyst and
> used in the gasoline distilling industry. Where a normal
> catalyst like platinum speeds up the rate of reaction and
> is unchanged at the end and so platinum is party to at
> least 3 molecules/atoms. If the Prusiner Model were
> correct then the world of chemistry has a Supercatalyst
> wherein it is party to only 2 molecules, not 3. And if
> platinum were a supercatalyst then it would be able to
> alter gold atoms into more platinum atoms.

Imagine crystallisation. You have a seed crystal of
chemicals arranged in an ordered array. chemicals free in
soluton interacyt with that crystal, and bind to it - the
heat given out from the intermolecular bond formation and
mayeb the increased entropy from the dissociation of bound
water molecules driving the reaction. Whats the difference
if you exchange the seed crystal for PrPSc and the chemical
in solution for PrPC? You berated me for not answering a
pointless question - I have mentioned the crystallisation
argument several times - now your turn to humour me
 
On Wed, 17 Mar 2004 01:59:09 +0000 (UTC), [email protected] wrote:

>A better example would be if platinum catalyzed the
>conversion of, let's say, platinum chloride into platinum
>and chlorine. Start out with a beaker of pure platinum
>chloride, let's say one molecule decomposes spontaneouely,
>producing a Pt atom. This atom catalyzes a second molecule,
>resulting in 2 Pt atoms. Then you'd get 4, 8, 16 and I'd
>guess the result is it would appear to suddenly decompose.

This is a chemical reaction with well-defined
thermodynamics.

PtCl2 ---> Pt + Cl2

or

PtCl4 ---> Pt + 2Cl2

In either case the reaction enthalpy is simply the negative
of the enthalpy of formation of PtCl2 or PtCl4,
respectively. The reaction energetics are independent of the
reaction mechansim; i.e., it does not matter if the process
is [auto]catalytic or not.

Steve Turner
 
"Archimedes Plutonium" <[email protected]> wrote in message
news:[email protected]...
> Bob <[email protected]> wrote in message
news:<[email protected]>...
> > On 15 Mar 2004 23:53:32 -0800, [email protected]
> > (Archimedes Plutonium) wrote:
> (some snipping)
> > >
> > >Would you not agree Bob that when two molecules collide
> > >and interact, that changes in one or both of the
> > >molecules is induced. That is normal collision and
> > >interaction. But would you not agree Bob that when a
> > >collision between protein molecules occurs and they
> > >interact and they go off as identical to one another,
> > >would you not agree that such was so implausible as to
> > >be unbelievable.
> >
> >
> > No, would not agree. But it has no relevance anyway.
> > That is not what happens. Prion A joins prion B, and
> > takes the B conformation (loosely).
> >
>
> Are you saying that prion A and prion B after the
> collision and interaction are not identical when they
> disjoin and move off? And that only a *part* of prion A is
> identical to a *part* of prion B? So the identicalness is
> not the entire prion molecule but only a small surface
> area of each molecule? If so, that would help explain
> better the thermodynamical energies and also explain
> better various prion variety types in that only a small
> portion of the prion is identical or made identical.
>
> I had always thought of the Prusiner Model as
> identicalness for the entire molecule. Partial
> identicalness could have a ring of truth. I guess partial
> identicalness could be the conversion of helices to that
> of sheets, so that a bad prion converts a portion of a
> helix into a sheet geometry.
>
> But I need to know something. Bob, can you tell me of the
> most similar protein molecule that behaves in this manner
> and is not prions. Tell me if there are any bio-molecules
> that act and behave in the manner of bad prions. Are there
> any? Or are bad prions a unique case.

If you'd read the link on serpins I sent you, then it would
help http://eagle.mmid.med.ualberta.ca/publications/JMB293p-
449.pdf Search for serpin and amyloid and see what you find
Might also help you develop your 'scissor' theory

> >
> > If you want to argue that mammalian prions may have
> > additional complexities (eg beyond yeast prions), fine.
> > It is true that no one has yet demonstrated conversion
> > to infective material in a cell-free system for a
> > mammalian prion. But the prion basics are amply
> > demonstrated, and there is no reason that the additional
> > complexities cannot be accommodated within the current
> > models. Time will tell.
> >
>
> The best explanation to date why infective material in a
> cell-free system is a no-go is that the disease is caused
> by the protein scissors and you need cells to create the
> scissors, and thus the disease is not caused by prion
> converting other prion particles, but that the scissors is
> the culprit.
>
> Bob, I have asked Wyrin whether the alpha-synuclein in
> Parkinsons and whether the two proteins that accumulate in
> Alzheimers come in several varieties and types. Or do they
> come in one and only one brand or type? Would you happen
> to know?

Define type. Both have conformational flexibility and the
ability to adopt a form that can aggregate into amyloid As
for strains of the disease, as seen with different
neuropathologies of prion disease, then no, not to the
same extent
 
[email protected] (Archimedes Plutonium) writes:

>[email protected] wrote in message
>news:<[email protected]>...

>> A better example would be if platinum catalyzed the
>> conversion of, let's say, platinum chloride into platinum
>> and chlorine. Start out with a beaker of pure platinum
>> chloride, let's say one molecule decomposes
>> spontaneouely, producing a Pt atom. This atom catalyzes a
>> second molecule, resulting in 2 Pt atoms. Then you'd get
>> 4, 8, 16 and I'd guess the result is it would appear to
>> suddenly decompose.

>I probably did not use the best example with platinum
>catalyzing gold into more platinum. I am after the numbers
>and chemists would never compute these numbers because they
>automatically know that it is impossible for such reactions
>to go forth. But I want the numbers so as to "emphasize and
>show how impossible".

Not only are such catalysts possible, but there is a term
for this process: autocatalysis. See
http://www.wikipedia.org/wiki/Autocatalysis. The example
that they give is 'tin pest', where in the cold, normal
metallic tin converts into grey tin. The grey tin is also a
catalyst for the process, so once started, the grey tin
catalyzes more metallic tin into grey tin and the process
speeds up until the tin object is destroyed.

>I could restate the problem by asking for platinum and
>gold mix and what energy it takes for a platinum atom to
>steal away a electron from a gold atom to make another
>platinum atom.

A Pt atom taking an electron away from gold would result in
two ions, Au+ and Pt-. The Au+ ion isn't a Pt atom, it is
still gold, so that is a poor example.

>Or I could ask for the energies involved in a CO and CO2
>mix where the CO converts CO2 into more CO.

>Or I could ask for the energies involved in ethylene-glycol
>to convert glycerol into more ethylene-glycol.

Look up 'tin pest' where grey tin converts metallic tin into
more grey tin.

>I am keeping focused on the main issue-- Supercatalysts --
>that they

Looks like the correct term is autocatalysts.
 
On 16 Mar 2004 23:28:25 -0800, [email protected] (Archimedes
Plutonium) wrote:

>I am keeping focused on the main issue-- Supercatalysts --
>that they do not exist because it takes too much energy for
>a molecule or atom that when it collides, it remains the
>same and yet still has energy coming from out of nowhere to
>convert other molecules into identical copies.

I believe the context here is prionic conversions?

What must be realized is the enormous conformational space
available to proteins. That is to say, there are potentially
thousands of different conformations available to a protein
---> which are all of very nearly equal energy <--- (note
emphasis!!!). Therefore, there is little if any energetic
penalty in converting one of these forms to another. This is
pure thermodynamics.

Thermodynamics alone, however, say nothing about how quickly
a transformation will occur, or whether it will occur at all
at a measurable rate. The classic example is oxidation of
diamond to carbon dioxide -- a process which is
thermodynamically downhill but which, under ordinary
circumstances, does not occur. It does not occur because the
energy barrier to the interconversion is too high. This
energy barrier is NOT the same thing as the reaction
enthalpy!!! And a high energy barrier does NOT mean that the
reaction is thermodynamically unfavorable!!!

This is where catalysts come in. A catalyst, almost by
definition, lowers the energy barrier to the reaction. It
cannot affect the overall reaction enthalpy; that would be
impossible. But it is perfectly reasonable for a catalyst to
lower the barrier such that a previously "impossible"
reaction goes quite smoothly. There are thousands of
examples of this.

One of these other examples is the following: any organic
chemist knows that amide bonds are very stable. In order to
break one, it is necessary to cook the amide with strong
acid or base, under very harsh conditions. But throw in the
right catalyst, such as a protease enzyme, and the reaction
proceeds quite nicely under the mildest conditions
imaginable - ambient temperature, neutral pH.

Steve Turner
 
"Wyrin" <[email protected]> wrote in message news:<[email protected]>...
> "Archimedes Plutonium" <[email protected]> wrote in
> message
> news:[email protected]...
> > Bob <[email protected]> wrote in message
> news:<[email protected]>...
> > > On 15 Mar 2004 23:53:32 -0800, [email protected]
> > > (Archimedes Plutonium) wrote:
> (some snipping)
> > > >
> > > >Would you not agree Bob that when two molecules
> > > >collide and interact, that changes in one or both of
> > > >the molecules is induced. That is normal collision
> > > >and interaction. But would you not agree Bob that
> > > >when a collision between protein molecules occurs and
> > > >they interact and they go off as identical to one
> > > >another, would you not agree that such was so
> > > >implausible as to be unbelievable.
> > >
> > >
> > > No, would not agree. But it has no relevance anyway.
> > > That is not what happens. Prion A joins prion B, and
> > > takes the B conformation (loosely).
> > >
> >
> > Are you saying that prion A and prion B after the
> > collision and interaction are not identical when they
> > disjoin and move off? And that only a *part* of prion A
> > is identical to a *part* of prion B? So the
> > identicalness is not the entire prion molecule but only
> > a small surface area of each molecule? If so, that would
> > help explain better the thermodynamical energies and
> > also explain better various prion variety types in that
> > only a small portion of the prion is identical or made
> > identical.
> >
> > I had always thought of the Prusiner Model as
> > identicalness for the entire molecule. Partial
> > identicalness could have a ring of truth. I guess
> > partial identicalness could be the conversion of helices
> > to that of sheets, so that a bad prion converts a
> > portion of a helix into a sheet geometry.
> >
> > But I need to know something. Bob, can you tell me of
> > the most similar protein molecule that behaves in this
> > manner and is not prions. Tell me if there are any bio-
> > molecules that act and behave in the manner of bad
> > prions. Are there any? Or are bad prions a unique case.
>
> If you'd read the link on serpins I sent you, then it
> would help http://eagle.mmid.med.ualberta.ca/publications-
> /JMB293p449.pdf Search for serpin and amyloid and see what
> you find Might also help you develop your 'scissor' theory
>

I feel somewhat guilty in calling it my "Scissors theory"
because I learned of scissors from the TV tube of a PBS
special on Alzheimers. But then again I do not feel guilty
to a large extent because when I began to seriously take on
the challenge of trying to solve the workings of Prion
disease back in 1997 with perhaps 2,000 to 5,000 posts on
the subject since then, I started with the idea of
"Manufacturing Sites" of prion proteins. I did not know that
in biological chemistry that proteins are routinely cut by
scissors. I just thought that prion proteins were created at
some manufacturing-site in the cells and that they thence
are wandered off or transported to the location where they
function as cell wall material. So that TV show taught me
that it is a Scissors and not a Manufacturing Site.

The other comment relates to the History of Prion disease in
that it sprang forth in the 1980s and 1990s when the
background community in medicine were seeped in viral causes
or bacteria causes and thus a majority portion of the
history of Prion disease was in a fighting arena of virus
versus nonvirus-protein-only.

When what should have happened, now that hindsight is 20/20,
is that Prion disease back in the 1980s should have looked
for its *Family Resemblance of Diseases*. We should not have
been looking so much for a virus, but instead have looked
for the diseases which most closely relate to Prion disease.
If we had done that in the 1980s we would have not looked
far to realize that Alzheimers and Parkinsons were that Family-Related-
Diseases. And from reading the reference that perhaps
Cirrhosis of the Liver is related to Prion, Alzheimers,
Parkinsons also.

The way to tackle new diseases of the future is to firstly
find the disease category that is a Family Resemblence and
thence borrow and analogize back and forth with the various
related diseases. If that had been done in 1980s when Prion
disease was beginning to appear, then no-one would have
made the gross hypothesis that the infectious agent was a
protein-only cause. Because they would then have been
obliged to say that Alzheimers is a protein-only caused
disease and that Parkinsons is a protein-only caused
disease when in fact it is a rogue Scissors that is the
causative agent of all three of these diseases. And that
the shape change of the bad proteins accumulating as waste
is just an incidental afteraffect and is almost irrelevant
to the cause of the diseases.

--- quoting in part from the reference that Wyrin posted
with no guarantee of correct spellings ---

The function of the serpins as proteinase inhibitors
depends.... Intermolecular loop insertion is known as serpin
polymerisation and results in a variety of diseases, most
notably liver cirrhosis resulting from mutations of the
prototypical serpin alpha_1-antitrypsin. --- end quoting ---

Wyrin, I am guessing that not only are Prion and
Parkinsons and Alzheimers belong into one huge FAmily
Related Diseases of old age where some Scissors in the
animal body becomes rogue and cuts proteins that have no
means of getting out of the body and hence accumulate as
waste material which kills the animal but that Liver
Cirrhosis also belongs to this same family of disease. And
there are probably many more that all belong together as
this one large class of diseases.

My main question now Wyrin, is what the Prion Scissors is,
its details and why is this scissors able to be eaten and
infect the animal whereas the Alzheimers and Parkinsons and
Liver Cirrhosis scissors is not eatable and thence
infectable.

ARchimedes Plutonium whole entire Universe is just one big
atom where dots of the electron-dot-cloud are galaxies
 
> > If you'd read the link on serpins I sent you, then it
> > would help http://eagle.mmid.med.ualberta.ca/publicatio-
> > ns/JMB293p449.pdf Search for serpin and amyloid and see
> > what you find Might also help you develop your 'scissor'
> > theory
> >
>
> I feel somewhat guilty in calling it my "Scissors theory"
> because I learned of scissors from the TV tube of a PBS
> special on Alzheimers. But then again I do not feel guilty
> to a large extent because when I began to seriously take
> on the challenge of trying to solve the workings of Prion
> disease back in 1997 with perhaps 2,000 to 5,000 posts on
> the subject since then, I started with the idea of
> "Manufacturing Sites" of prion proteins. I did not know
> that in biological chemistry that proteins are routinely
> cut by scissors. I just thought that prion proteins were
> created at some manufacturing-site in the cells and that
> they thence are wandered off or transported to the
> location where they function as cell wall material. So
> that TV show taught me that it is a Scissors and not a
> Manufacturing Site.
>
> The other comment relates to the History of Prion disease
> in that it sprang forth in the 1980s and 1990s when the
> background community in medicine were seeped in viral
> causes or bacteria causes and thus a majority portion of
> the history of Prion disease was in a fighting arena of
> virus versus nonvirus-protein-only.
>
> When what should have happened, now that hindsight is
> 20/20, is that Prion disease back in the 1980s should have
> looked for its *Family Resemblance of Diseases*. We should
> not have been looking so much for a virus, but instead
> have looked for the diseases which most closely relate to
> Prion disease. If we had done that in the 1980s we would
> have not looked far to realize that Alzheimers and
> Parkinsons were that Family-Related-Diseases. And from
> reading the reference that perhaps Cirrhosis of the Liver
> is related to Prion, Alzheimers, Parkinsons also.
>
> The way to tackle new diseases of the future is to firstly
> find the disease category that is a Family Resemblence and
> thence borrow and analogize back and forth with the
> various related diseases. If that had been done in 1980s
> when Prion disease was beginning to appear, then no-one
> would have made the gross hypothesis that the infectious
> agent was a protein-only cause. Because they would then
> have been obliged to say that Alzheimers is a protein-only
> caused disease and that Parkinsons is a protein-only
> caused disease when in fact it is a rogue Scissors that is
> the causative agent of all three of these diseases. And
> that the shape change of the bad proteins accumulating as
> waste is just an incidental afteraffect and is almost
> irrelevant to the cause of the diseases.
>
> --- quoting in part from the reference that Wyrin posted
> with no guarantee of correct spellings ---
>
> The function of the serpins as proteinase inhibitors
> depends.... Intermolecular loop insertion is known as
> serpin polymerisation and results in a variety of
> diseases, most notably liver cirrhosis resulting from
> mutations of the prototypical serpin alpha_1-antitrypsin.
> --- end quoting ---
>
> Wyrin, I am guessing that not only are Prion and
> Parkinsons and Alzheimers belong into one huge FAmily
> Related Diseases of old age where some Scissors in the
> animal body becomes rogue and cuts proteins that have no
> means of getting out of the body and hence accumulate as
> waste material which kills the animal but that Liver
> Cirrhosis also belongs to this same family of disease. And
> there are probably many more that all belong together as
> this one large class of diseases.

The idea that amyloid disease have a lot in common is
nothing new. The main idea behind this however, is not about
he scissors/proteases, but inherent properties of the
protein sequence that allow it to adopt a partially stable
intermediate conformation

U=unfolded. I=partially stable intermediate, F=correct
folded form prsent in healthy cell with healthy function

U <->I<->F

If the cellular conditions change eg due to damage, the I
form can accumulate. When its levels reach a certain point,
the I form can aggregate into amyloid. Now, protease could
come into this in several ways either aberrant activity by
scissors/proteases on F causes and increase in the I form or
the I form isnt broken down by the scissors and so isnt
cleared from the cell and builds up There is a lot of
evidence that damaged proteins (eg under oxidative stress
conditions) become resistant to protease degradation)

> My main question now Wyrin, is what the Prion Scissors is,
> its details and why is this scissors able to be eaten and
> infect the animal whereas the Alzheimers and Parkinsons
> and Liver Cirrhosis scissors is not eatable and thence
> infectable.

The next thing I would suggest you search on is Ubiquitin
and proteosome - one of the systems in the cell for
degrading damaged proteins. I am not sure about any specific
proteases known to act on PrPC, but PrPC and PrPSc are
differently degraded Within the brain, PrPC is processed
under normal conditions into a C-terminal fragment, with an
N-terminus starting at residues corresponding to His-114 or
Val-115 in the ovine sequence (Chen et al., 1995). In
diseased brains, the processed fragment is longer and toxic,
with the hydrophobic sequence (109-129) intact. This
hydrophobic sequence on its own is neurotoxic

Note that no protease activity has been found associtaed
with brain smaples enriched for infectivity - but PrPSc has.
 
On 17 Mar 2004 23:45:36 -0800, [email protected] (Archimedes
Plutonium) wrote:

>Bob <[email protected]> wrote in message
>news:<[email protected]>...
>> On 15 Mar 2004 23:53:32 -0800, [email protected]
>> (Archimedes Plutonium) wrote:
>(some snipping)
>> >
>> >Would you not agree Bob that when two molecules collide
>> >and interact, that changes in one or both of the
>> >molecules is induced. That is normal collision and
>> >interaction. But would you not agree Bob that when a
>> >collision between protein molecules occurs and they
>> >interact and they go off as identical to one another,
>> >would you not agree that such was so implausible as to
>> >be unbelievable.
>>
>>
>> No, would not agree. But it has no relevance anyway. That
>> is not what happens. Prion A joins prion B, and takes the
>> B conformation (loosely).
>>
>
>Are you saying that prion A and prion B after the collision
>and interaction are not identical when they disjoin and
>move off? And that only a *part* of prion A is identical to
>a *part* of prion B? So the identicalness is not the entire
>prion molecule but only a small surface area of each
>molecule? If so, that would help explain better the
>thermodynamical energies and also explain better various
>prion variety types in that only a small portion of the
>prion is identical or made identical.
>
>I had always thought of the Prusiner Model as identicalness
>for the entire molecule. Partial identicalness could have a
>ring of truth. I guess partial identicalness could be the
>conversion of helices to that of sheets, so that a bad
>prion converts a portion of a helix into a sheet geometry.
>

You are on the right track. The key demonstrated fact is the
helix --> sheet conversion. The whole notion that a protein
has "a" conformation is a simplification.

>But I need to know something. Bob, can you tell me of the
>most similar protein molecule that behaves in this manner
>and is not prions.

That really is a vague question. What manner? If that is
the definition of a prion, then any protein that does it
is a prion.

But perhaps more importantly... protein shapes are elusive.
Usually we do not know the shape of a protein. We know its
function. Prions came to our attention because they cause a
disease. Over time we gather some info about their
structure.

The first "complete" info about protein structure came only
in the 1950s. In the 60s we began to realize that proteins
are flexible, and have multiple shapes of bio relevance.

So aside from being picky as to exactly what your Q is, it
is probably not really answerable, for shortage of info.

Ok, so you now understand that everything in the prion
model is "reasonable" (does not violate any laws). And you
should understand that all aspects have been demonstrated
in one place or another, most clearly with yeast.
(Biologists often work on simple systems first.) Now, how
much more is going on with mammalian prion diseases, time
will tell. Let's wait.

bob
 
"Wyrin" <[email protected]> wrote in message
news:<[email protected]>... (snipped)
> The idea that amyloid disease have a lot in common is
> nothing new. The main idea behind this however, is not
> about he scissors/proteases, but inherent properties of
> the protein sequence that allow it to adopt a partially
> stable intermediate conformation
>

When you say protein-sequence, do you mean where proteins
are manufactured? So I have a distinction between the
creation of 2 types of proteins. One is cut from a scissors
and that other is manufactured by the DNA, RNA machinery.

So I would see 3 Models for prion disease:
(1) Prusiner model where bad prions change good prions
(2) Scissors model where a protease scissors encounters
an already existing protein and cuts it forming 2
new proteins
(3) Manufacturing Site model where proteins are produced
like an assembly line from the DNA and RNA

So that Alzheimers and Parkinsons fit best into (3)

> U=unfolded. I=partially stable intermediate, F=correct
> folded form prsent in healthy cell with healthy function
>
> U <->I<->F
>

Stability makes sense in the fact these diseases afflict old
age mostly.

I wonder if the lowest level of discussing these diseases is
the level where we talk mostly about the hydrogen bonds that
comprise these proteins. I wonder if hydrogen bonds make up
a majority of the surface geometry of these proteins and
thus the main determinant of their functionality.

> If the cellular conditions change eg due to damage, the I
> form can accumulate. When its levels reach a certain
> point, the I form can aggregate into amyloid. Now,
> protease could come into this in several ways either
> aberrant activity by scissors/proteases on F causes and
> increase in the I form or the I form isnt broken down by
> the scissors and so isnt cleared from the cell and builds
> up There is a lot of evidence that damaged proteins (eg
> under oxidative stress conditions) become resistant to
> protease degradation)
>
> > My main question now Wyrin, is what the Prion Scissors
> > is, its details and why is this scissors able to be
> > eaten and infect the animal whereas the Alzheimers and
> > Parkinsons and Liver Cirrhosis scissors is not eatable
> > and thence infectable.
>
> The next thing I would suggest you search on is Ubiquitin
> and proteosome - one of the systems in the cell for
> degrading damaged proteins.

Have looked at some websites on Ubiquitin. Need to see more
before I can comment.

> I am not sure about any specific proteases known to act on
> PrPC, but PrPC and PrPSc are differently degraded Within
> the brain, PrPC is processed under normal conditions into
> a C-terminal fragment, with an N-terminus starting at
> residues corresponding to His-114 or Val-115 in the ovine
> sequence (Chen et al., 1995). In diseased brains, the
> processed fragment is longer and toxic, with the
> hydrophobic sequence (109-129) intact. This hydrophobic
> sequence on its own is neurotoxic
>
> Note that no protease activity has been found
> associtaed with brain smaples enriched for infectivity
> - but PrPSc has.

Okay, if no protease activity found, would imply no scissors
involved. But it still leaves the question of model of
Prusiner versus model of Manufacturing Site.

I find the Manufacturing Site a more elegant model than
Prusiner, because it is much more simple. It is like a
corrupted cookie cutter that spews out numerous misshapened
proteins. Rather than each PrPSc changing each PrPC. The
Manufacturing Site or cookie-cutter could be corrupted by
bad prions.

It stands to reason that the body produces good prions, so
the Manufacturing Site must exist. Once the protein is
produced, I wonder how it is moved into the jobsite for it
to carry out its function? I have trouble picturing Manufacturing-
sites for proteins whereas there is little difficulty in
picturing Scissors in cells.

Archimedes Plutonium whole entire Universe is just one big
atom where dots of the electron-dot-cloud are galaxies
 
"Wyrin" <[email protected]> wrote in message news:<[email protected]>...

>
> The next thing I would suggest you search on is Ubiquitin
> and proteosome - one of the systems in the cell for
> degrading damaged proteins. I am not sure about any
> specific proteases known to act on PrPC, but PrPC and
> PrPSc are differently degraded Within the brain, PrPC is
> processed under normal conditions into a C-terminal
> fragment, with an N-terminus starting at residues
> corresponding to His-114 or Val-115 in the ovine sequence
> (Chen et al., 1995). In diseased brains, the processed
> fragment is longer and toxic, with the hydrophobic
> sequence (109-129) intact. This hydrophobic sequence on
> its own is neurotoxic
>
> Note that no protease activity has been found
> associtaed with brain smaples enriched for infectivity
> - but PrPSc has.

Wyrin, it sounds as though scientists know more about
protease activity than they know about the sequence of
events leading up the creation of new PrPC by the DNA/RNA
sequencing which I call the Manufacturing-Site of PrPC.

Wyrin, when a new PrPC is made by a cell, does it have far
to travel to get to the place where it will serve its
purpose? And how do proteins travel and move around in the
cell to get where their jobsite is located? This is highly
relevant to distinguish the Prusiner Model from the
Manufacturing Site Model for how does one explain PrPSc
altering PrPC if a lot of roaming and traveling around is
involved for the bad prion. Whereas if the disease locus is
the Manufacturing Site then like a cookie cutter it spews
out deformed prions.

One possibility is that the bad prion does not alter good
prions but rather instead like flack gets stuck in the
DNA/RNA sequencing and deforms the Manufacturing Site.

So the picture that yields is the bad prion changes the
Manufacturing Site, never the good prions.

Archimedes Plutonium whole entire Universe is just one big
atom where dots of the electron-dot-cloud are galaxies
 
On 21 Mar 2004 22:19:32 -0800, [email protected] (Archimedes
Plutonium) wrote:

>Wyrin, when a new PrPC is made by a cell, does it have far
>to travel to get to the place where it will serve its
>purpose? And how do proteins travel and move around in the
>cell to get where their jobsite is located? This is highly
>relevant to distinguish the Prusiner Model from the
>Manufacturing Site Model for how does one explain PrPSc
>altering PrPC if a lot of roaming and traveling around is
>involved for the bad prion. Whereas if the disease locus is
>the Manufacturing Site then like a cookie cutter it spews
>out deformed prions.
>

It would help if you would speak biology. No idea what you
refer to as mfg site. Proteins are assembled from amino
acids, using DNA instruction. Then there is much processing
and folding and transport. Anywhere along this line there
could be a place where interaction of nascent PrC and PrSc
is more likely to occur and make the deleterious prion form.
It might have been as simple as interaction of PrSc with
mature PrC. But perhaps it is not. (We know such interaction
can occur, but at least so far that has not been
demonstrated to create infectious agents.)

>One possibility is that the bad prion does not alter good
>prions but rather instead like flack gets stuck in the
>DNA/RNA sequencing and deforms the Manufacturing Site.

That is a quite remote possibility. We know the amino acid
sequence is normal. And we know good and bad prions
interact. So proposing something like this is way out in
left field. Just doesn't fit.

bob
 
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