how many varieties does alpha-synuclein come in; Question to Wyrin

Discussion in 'Health and medical' started by Archimedes Plut, Mar 19, 2004.

  1. "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]>...
    > > > "Archimedes Plutonium" <[email protected]> wrote
    > > > in message news:[email protected]
    > > > google.com...
    > > > > "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/publica-
    > > > > > tions/JMB293p449.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/annu-
    > rev.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)
    >

    Well, that is nice to know, I assume you are Colin from
    Cambridge Univ in England. But it saddens me to realize that
    your earning of a degree in science is grounded in
    pseudoscience of Prion theory.

    Remember, Colin, or Wyrin if not Colin, that you entered my
    thread discussion with flinging of mud at me and no good
    objective scientists enters a discussion of science by
    hurdling mud and flinging of attack. So you should not be
    surprized that I gave you an overdose of your own medicine.

    I love doing science and can be 100% objective as my below
    question shows you. And if anything that I can teach you,
    Wyrin is that you need to work on your science objectivity
    and leave your personal subjective and ad hominem elsewhere.
    I too am no angel as far as ad hominem, but keep in mind
    that I seldom use ad hominem unless others who have started
    the flinging and brawl. You threw the first punches Wyrin
    and so you are most at blame.

    But please look at my below question.

    > > > 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

    Colin, or Wyrin if not Colin. Back around 1999 or
    thereabouts give or take a few years I seem to remember
    these facts. Please correct them if wrong.

    I remember the data that CJD in humans comes in at least 6
    or 7 varieties or different types so we can say there is
    CJD_1 and CJD_2, CJD_3, CJD_4, CJD_5, CJD_6.

    And I remember the data that Mad Cow Disease comes in 13
    different varieties or types of MCD_1, MCD_2, ....MCD_13.

    Wyrin is that data correct or have I got it wrong as to the
    number of varieties and what is the current number of types
    of CJD and MCD?

    Second Question:

    In Parkinsons disease there is the accumulation of unwanted
    alpha-synuclein. Please tell me Wyrin, how many different
    varieties or types of AS there are in connection with
    Parkinsons disease. Does it come singular or are there
    several different types?

    Third Question:

    In Alzheimers disease there are two unwanted proteins that
    accumulate, and sorry to say I forgotten the specific
    science name for those two proteins and let me just call
    them Alzh-beta and Alzh-alpha. Please remind me of their
    full science names or abbreviations. But my main question
    about them is whether they come in a variety of types and
    not singular? Does the Alzheimer beta-amyloid come in say
    two or three or four or five or six or seven different
    variety types??

    Please, Wyrin, let us start this conversation over
    between the two of us where we stick plainly to the
    objective science.

    ARchimedes Plutonium whole entire Universe is just one big
    atom where dots of the electron-dot-cloud are galaxies
     
    Tags:


  2. Wyrin

    Wyrin Guest

    "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]>...
    > > > > "Archimedes Plutonium" <[email protected]>
    > > > > wrote in message news:[email protected]
    > > > > posting.google.com...
    > > > > > "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/publi-
    > > > > > > cations/JMB293p449.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
    io.
    > > > > > 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)
    > >
    >
    >
    > Well, that is nice to know, I assume you are Colin from
    > Cambridge Univ in England. But it saddens me to realize
    > that your earning of a degree in science is grounded in
    > pseudoscience of Prion theory.

    I'm not, but I know him. And quit the personal attacks. You
    know nothing of my degree and its relation to prion theory
    (which it casts some doubt on). Kindly quit questioning
    objectivity and refer me to scientific papaers that support
    your argument as I have done - like a good scientist.

    > Remember, Colin, or Wyrin if not Colin, that you entered
    > my thread discussion with flinging of mud at me and no
    > good objective scientists enters a discussion of science
    > by hurdling mud and flinging of attack. So you should not
    > be surprized that I gave you an overdose of your own
    > medicine.

    I entered this by giving you references to experimental data
    - which I have previously done before. No mud involved

    > I love doing science and can be 100% objective as my below
    > question shows you. And if anything that I can teach you,
    > Wyrin is that you need to work on your science objectivity
    > and leave your personal subjective and ad hominem
    > elsewhere. I too am no angel as far as ad hominem, but
    > keep in mind that I seldom use ad hominem unless others
    > who have started the flinging and brawl. You threw the
    > first punches Wyrin and so you are most at blame.

    please point these out. My first post to you on this recent
    topic: "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"

    I see no ad hominen attacks in there at all. Anyway...

    > But please look at my below question.

    > >
    > > 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
    >
    > Colin, or Wyrin if not Colin. Back around 1999 or
    > thereabouts give or take a few years I seem to remember
    > these facts. Please correct them if wrong.
    >
    > I remember the data that CJD in humans comes in at least 6
    > or 7 varieties or different types so we can say there is
    > CJD_1 and CJD_2, CJD_3, CJD_4, CJD_5, CJD_6.
    >
    > And I remember the data that Mad Cow Disease comes in 13
    > different varieties or types of MCD_1, MCD_2, ....MCD_13.
    > Wyrin is that data correct or have I got it wrong as to
    > the number of varieties and what is the current number of
    > types of CJD and MCD?
    >

    The main problem with your three questions is that you need
    to definevariety/type. Do you mean variety based on symptoms
    of disease, or the neuropathology in the brain? Or
    mutational vareities of the protein? Conformational
    varieties? This needs to be specified. There are several
    mutants of PrP that can predisposed animals to disease. A
    good general resource it http://www.mad-
    cow.org/00/sci_archive_frame.html See http://www.mad-
    cow.org/00/topics.html#fa for examples of the many different
    mutants involved with familial CJD

    > Second Question:
    >
    > In Parkinsons disease there is the accumulation of
    > unwanted alpha-synuclein. Please tell me Wyrin, how many
    > different varieties or types of AS there are in connection
    > with Parkinsons disease. Does it come singular or are
    > there several different types?

    See above. Prion is my area, but I have some peripheral
    knowledge about other neurodegenerative diseases such as
    Alzheimers, Parkinsons, Huntingtons and ALS. I only know a
    little about alpha-synuclein in that oxidative stress -
    induced modification of it is beleieved to be a major cause
    of aggregation. However, I suspect this to be largely true
    for other neurodegenerative disorders too

    > Third Question:
    >
    > In Alzheimers disease there are two unwanted proteins that
    > accumulate, and sorry to say I forgotten the specific
    > science name for those two proteins and let me just call
    > them Alzh-beta and Alzh-alpha. Please remind me of their
    > full science names or abbreviations. But my main question
    > about them is whether they come in a variety of types and
    > not singular? Does the Alzheimer beta-amyloid come in say
    > two or three or four or five or six or seven different
    > variety types??

    I think you mean tau and AmyloidBeta. Again you need to be
    specific in 'type'. I suppose tau could be thought of as
    coming in two types: normal and aberrantly phosphorylated

    > Please, Wyrin, let us start this conversation over between
    > the two of us where we stick plainly to the objective
    > science.

    happily. But understand my need for claims to be backed upa
    with reference to scientific literature
     
  3. Wyrin

    Wyrin Guest

    > I remember the data that CJD in humans comes in at least 6
    > or 7 varieties or different types so we can say there is
    > CJD_1 and CJD_2, CJD_3, CJD_4, CJD_5, CJD_6.
    >
    > And I remember the data that Mad Cow Disease comes in 13
    > different varieties or types of MCD_1, MCD_2, ....MCD_13.
    >
    > Wyrin is that data correct or have I got it wrong as to
    > the number of varieties and what is the current number of
    > types of CJD and MCD?
    >

    Further to my other post, pointing out the need to define
    type and variety:

    Nature has just published some work dealing with the strains
    of prions - 'type' determined by conformation

    Conformational variations in an infectious protein determine
    prion strain differences

    MOTOMASA TANAKA1, PETER CHIEN1,2, NARIMAN NABER3, ROGER
    COOKE3 & JONATHAN S. WEISSMAN1,2

    A remarkable feature of prion biology is the strain
    phenomenon wherein prion particles apparently composed of
    the same protein lead to phenotypically distinct
    transmissible states. To reconcile the existence of strains
    with the 'protein-only' hypothesis of prion transmission, it
    has been proposed that a single protein can misfold into
    multiple distinct infectious forms, one for each different
    strain. Several studies have found correlations between
    strain phenotypes and conformations of prion particles;
    however, whether such differences cause or are simply a
    secondary manifestation of prion strains remains unclear,
    largely due to the difficulty of creating infectious
    material from pure protein. Here we report a high-efficiency
    protocol for infecting yeast with the [PSI+] prion using
    amyloids composed of a recombinant Sup35 fragment (Sup-NM).
    Using thermal stability and electron paramagnetic resonance
    spectroscopy, we demonstrate that Sup-NM amyloids formed at
    different temperatures adopt distinct, stably propagating
    conformations. Infection of yeast with these different
    amyloid conformations leads to different [PSI+] strains.
    These results establish that Sup-NM adopts an infectious
    conformation before entering the cell-fulfilling a key
    prediction of the prion hypothesis-and directly demonstrate
    that differences in the conformation of the infectious
    protein determine prion strain variation.
     
  4. Wyrin

    Wyrin Guest

    "Wyrin" <[email protected]> wrote in message
    news:[email protected]...
    > > I remember the data that CJD in humans comes in at least
    > > 6 or 7 varieties or different types so we can say there
    > > is CJD_1 and CJD_2, CJD_3, CJD_4, CJD_5, CJD_6.
    > >
    > > And I remember the data that Mad Cow Disease comes in 13
    > > different varieties or types of MCD_1, MCD_2,
    > > ....MCD_13.
    > >
    > > Wyrin is that data correct or have I got it wrong as to
    > > the number of varieties and what is the current number
    > > of types of CJD and MCD?
    > >
    >
    > Further to my other post, pointing out the need to define
    > type and
    variety:
    >
    > Nature has just published some work dealing with the
    > strains of prions - 'type' determined by conformation
    >
    > Conformational variations in an infectious protein
    > determine prion strain differences
    >
    > MOTOMASA TANAKA1, PETER CHIEN1,2, NARIMAN NABER3, ROGER
    > COOKE3 & JONATHAN
    S.
    > WEISSMAN1,2
    >
    > A remarkable feature of prion biology is the strain
    > phenomenon wherein
    prion
    > particles apparently composed of the same protein lead to
    > phenotypically distinct transmissible states. To reconcile
    > the existence of strains with the 'protein-only'
    > hypothesis of prion transmission, it has been proposed
    > that a single protein can misfold into multiple distinct
    > infectious forms, one for each different strain. Several
    > studies have found correlations between strain phenotypes
    > and conformations of prion particles; however, whether
    > such differences cause or are simply a secondary
    > manifestation of prion strains remains unclear, largely
    > due to the difficulty of creating infectious material from
    > pure protein. Here we report a high-efficiency protocol
    > for infecting yeast with the [PSI+] prion using amyloids
    > composed of a recombinant Sup35 fragment (Sup-NM). Using
    > thermal stability and electron paramagnetic resonance
    > spectroscopy, we demonstrate that Sup-NM amyloids formed
    > at different temperatures adopt distinct, stably
    propagating
    > conformations. Infection of yeast with these
    > different amyloid
    conformations
    > leads to different [PSI+] strains. These results establish
    > that Sup-NM adopts an infectious conformation before
    > entering the cell-fulfilling a
    key
    > prediction of the prion hypothesis-and directly
    > demonstrate that
    differences
    > in the conformation of the infectious protein determine
    > prion strain variation.

    here's the link http://www.nature.com/nature/links/040318/040318-
    9.html
     
  5. "Wyrin" <[email protected]> wrote in message news:<[email protected]>...

    > >
    > > I remember the data that CJD in humans comes in at least
    > > 6 or 7 varieties or different types so we can say there
    > > is CJD_1 and CJD_2, CJD_3, CJD_4, CJD_5, CJD_6.
    > >
    > > And I remember the data that Mad Cow Disease comes in 13
    > > different varieties or types of MCD_1, MCD_2,
    > > ....MCD_13. Wyrin is that data correct or have I got it
    > > wrong as to the number of varieties and what is the
    > > current number of types of CJD and MCD?
    > >
    >
    > The main problem with your three questions is that you
    > need to definevariety/type. Do you mean variety based on
    > symptoms of disease, or the neuropathology in the brain?
    > Or mutational vareities of the protein? Conformational
    > varieties? This needs to be specified. There are several
    > mutants of PrP that can predisposed animals to disease. A
    > good general resource it http://www.mad-
    > cow.org/00/sci_archive_frame.html See http://www.mad-
    > cow.org/00/topics.html#fa for examples of the many
    > different mutants involved with familial CJD
    >

    I am really not sure of what I mean as far as detail. I
    remember the numerous types of varieties of prion proteins
    is a *huge problem* for the Prusiner Model. With my Scissors-
    theory that the cause of these diseases is not the
    accumulating protein but the scissors that cuts the
    proteins. Thus, I need to see if Alzheimers, Parkinsons has
    a *similar* proliferation in types or varieties as does
    Prion disease. But reading many of your posts of today I get
    the firm suspicion that Alzheimers and Parkinsons has just
    as many if not more varieties of rogue proteins of the
    protein waste accumulation.

    My problem is that I am not intimate-knowledge of the
    cutting edge of data and information on these 3
    diseases. Virtually all of my posts are predicated on
    sit-at-home Logic. Sort of like a Sherlock Holmes that
    never gets out to the scenes of the crime but is fed
    information at his office.

    > > Second Question:
    > >
    > > In Parkinsons disease there is the accumulation of
    > > unwanted alpha-synuclein. Please tell me Wyrin, how many
    > > different varieties or types of AS there are in
    > > connection with Parkinsons disease. Does it come
    > > singular or are there several different types?
    >
    > See above. Prion is my area, but I have some peripheral
    > knowledge about other neurodegenerative diseases such as
    > Alzheimers, Parkinsons, Huntingtons and ALS. I only know a
    > little about alpha-synuclein in that oxidative stress -
    > induced modification of it is beleieved to be a major
    > cause of aggregation. However, I suspect this to be
    > largely true for other neurodegenerative disorders too
    >

    Good, so alpha-synuclein may not have as many different
    varieties or types as PrP in prion disease but that
    Parkinsons does display a spectrum range of varieties and
    types that Prion disease displays. Hopefully someone can
    tell us specific numbers such as say Prion CJD had at least
    7 varieties at last count and the say Parkinsons has at
    least 3 varieties at last count.

    > > Third Question:
    > >
    > > In Alzheimers disease there are two unwanted proteins
    > > that accumulate, and sorry to say I forgotten the
    > > specific science name for those two proteins and let me
    > > just call them Alzh-beta and Alzh-alpha. Please remind
    > > me of their full science names or abbreviations. But my
    > > main question about them is whether they come in a
    > > variety of types and not singular? Does the Alzheimer
    > > beta-amyloid come in say two or three or four or five or
    > > six or seven different variety types??
    >
    > I think you mean tau and AmyloidBeta. Again you need to be
    > specific in 'type'. I suppose tau could be thought of as
    > coming in two types: normal and aberrantly phosphorylated
    >

    Yes, thanks, sorry but I am troubled with having to do work
    in all sciences ranging from Physics to Poetry with every
    other science in between those two and often is difficult
    for me to remember specifics as I jump from one science to
    another. After I made my post yesterday, my brain remembered
    "tau" but it was too late. And I do remember that in the
    last several decades the bio-medical community was stuck in
    a rut over thinking whether tau came first or beta-amyloid
    and what the relationship between those two were. So that
    the history of Alzheimers for the past 20 years could be
    said to be one of trying to understand the why of these 2
    different proteins. Wyrin, when I watched the TV program on
    Alzheimers with its rogue scissors cutting leaving a beta-
    amyloid fragment that will accumulate as waste, in that
    program never once was mentioned the Tau particle. Perhaps
    the scissors when it creates the beta-amyloid that the tau
    particle was the longer protein fragment. Anyway, after
    watching that program I am unclear as to where the Tau
    protein is created.

    >
    > > Please, Wyrin, let us start this conversation over
    > > between the two of us where we stick plainly to the
    > > objective science.
    >
    > happily. But understand my need for claims to be backed
    > upa with reference to scientific literature

    I may not be able to please you on that as I am not actually
    working hands on in a lab over any of these issues. I have
    more questions than answers. I am more of a Logician piecing
    together data that I get from people who actually are
    working in the laboratory. Wyrin, mine is new theory and so
    there is no reference or literature usually.

    Question: can you point me to a website that tells me
    specifically how many types or varieties of beta-amyloid in
    Alzheimers, how many PrP in Prion of (1) CJD (2) Mad Cow (3)
    sheep scrapie, and how many varieties and types in alpha-
    synuclein for Parkinsons.

    I had read parts of your serpin and will make a new post for
    this is already too long.

    Archimedes Plutonium whole entire Universe is just one big
    atom where dots of the electron-dot-cloud are galaxies
     
  6. "Wyrin" <[email protected]> wrote in message news:<[email protected]>...
    > > I remember the data that CJD in humans comes in at least
    > > 6 or 7 varieties or different types so we can say there
    > > is CJD_1 and CJD_2, CJD_3, CJD_4, CJD_5, CJD_6.
    > >
    > > And I remember the data that Mad Cow Disease comes in 13
    > > different varieties or types of MCD_1, MCD_2,
    > > ....MCD_13.
    > >
    > > Wyrin is that data correct or have I got it wrong as to
    > > the number of varieties and what is the current number
    > > of types of CJD and MCD?
    > >
    >
    > Further to my other post, pointing out the need to define
    > type and variety:
    >
    > Nature has just published some work dealing with the
    > strains of prions - 'type' determined by conformation
    >
    > Conformational variations in an infectious protein
    > determine prion strain differences
    >
    > MOTOMASA TANAKA1, PETER CHIEN1,2, NARIMAN NABER3, ROGER
    > COOKE3 & JONATHAN S. WEISSMAN1,2
    >
    > A remarkable feature of prion biology is the strain
    > phenomenon wherein prion particles apparently composed of
    > the same protein lead to phenotypically distinct
    > transmissible states. To reconcile the existence of
    > strains with the 'protein-only' hypothesis of prion
    > transmission, it has been proposed that a single protein
    > can misfold into multiple distinct infectious forms, one
    > for each different strain. Several studies have found
    > correlations between strain phenotypes and conformations
    > of prion particles; however, whether such differences
    > cause or are simply a secondary manifestation of prion
    > strains remains unclear, largely due to the difficulty of
    > creating infectious material from pure protein. Here we
    > report a high-efficiency protocol for infecting yeast with
    > the [PSI+] prion using amyloids composed of a recombinant
    > Sup35 fragment (Sup-NM). Using thermal stability and
    > electron paramagnetic resonance spectroscopy, we
    > demonstrate that Sup-NM amyloids formed at different
    > temperatures adopt distinct, stably propagating
    > conformations. Infection of yeast with these different
    > amyloid conformations leads to different [PSI+] strains.
    > These results establish that Sup-NM adopts an infectious
    > conformation before entering the cell-fulfilling a key
    > prediction of the prion hypothesis-and directly
    > demonstrate that differences in the conformation of the
    > infectious protein determine prion strain variation.

    Thank you Wyrin, that is indeed very helpful. The way I
    would read the above is that the INFECTIVE agent is not the
    prion particle but the scissors that cuts prions. In the
    1990s and especially 1997 when discussing prion disease with
    mostly Bob Bruner of Berkeley I always spoke of
    "Manufacturing Site" because I was never really trained into
    biology in details to know or realize or understand that the
    creation of proteins in the body of animals is one of usual
    encountering of not a Manufacturing Site like a factory
    producing raw materials but rather one of a Scissors going
    around in the body of animals that cuts proteins.

    So reading the above Wyrin, I would say the Infective Agent
    is a protein scissors and the various strains or types or
    varieties of prion proteins is a result of these rogue
    proteins able to change themselves.

    So that anyone can take the above NATURE article and cut and
    paste Alzheimers with its tau and beta-amyloid. Scissors
    cause Prion disease and scissors cause Alzheimers and that
    once those rogue scissors create a rogue tau protein or a
    rogue beta-amyloid protein, each of those rogue tau proteins
    or beta-amyloid proteins comes into contact with a like or
    similar protein they can thence increase the strains or
    types or varieties of those tau or beta-amyloid proteins.

    But the essentialness of the disease is that the Scissors is
    the infective agent.

    Apparently in Prion disease such as CJD or Mad-Cow or sheep-
    scrapie those rogue Scissors are transmittable and have easy
    passage into the brain from the blood brain barrier. Whereas
    the Scissors of Alzheimers or Parkinsons seems to be unable
    to be contagious and unable to enter the brain from the blood-
    brain barrier. Perhaps the Scissors of Alzheimers and
    Parkinsons is such a huge protein molecule whereas the Prion
    scissors is a relatively smallish molecule.

    Wyrin, is there any research as to a Prion scissors? The
    size of the scissors and whether the scissors is very
    different for scrapie, CJD and Mad Cow disease?

    Wyrin, is there any news of a Scissors that cuts the alpha-
    synuclein?

    Also I would wonder the relationship of metal-ions to these
    Scissors, especially magnetic-manganese.

    ARchimedes Plutonium whole entire Universe is just one big
    atom where dots of the electron-dot-cloud are galaxies
     
  7. Bob

    Bob Guest

    On 18 Mar 2004 11:16:13 -0800, [email protected] (Archimedes
    Plutonium) wrote:

    >> Nature has just published some work dealing with the
    >> strains of prions - 'type' determined by conformation
    >>
    >> Conformational variations in an infectious protein
    >> determine prion strain differences
    >>
    >> MOTOMASA TANAKA1, PETER CHIEN1,2, NARIMAN NABER3, ROGER
    >> COOKE3 & JONATHAN S. WEISSMAN1,2
    >>
    >> A remarkable feature of prion biology is the strain
    >> phenomenon wherein prion particles apparently composed of
    >> the same protein lead to phenotypically distinct
    >> transmissible states. To reconcile the existence of
    >> strains with the 'protein-only' hypothesis of prion
    >> transmission, it has been proposed that a single protein
    >> can misfold into multiple distinct infectious forms, one
    >> for each different strain. Several studies have found
    >> correlations between strain phenotypes and conformations
    >> of prion particles; however, whether such differences
    >> cause or are simply a secondary manifestation of prion
    >> strains remains unclear, largely due to the difficulty of
    >> creating infectious material from pure protein. Here we
    >> report a high-efficiency protocol for infecting yeast
    >> with the [PSI+] prion using amyloids composed of a
    >> recombinant Sup35 fragment (Sup-NM). Using thermal
    >> stability and electron paramagnetic resonance
    >> spectroscopy, we demonstrate that Sup-NM amyloids formed
    >> at different temperatures adopt distinct, stably
    >> propagating conformations. Infection of yeast with these
    >> different amyloid conformations leads to different [PSI+]
    >> strains. These results establish that Sup-NM adopts an
    >> infectious conformation before entering the cell-
    >> fulfilling a key prediction of the prion hypothesis-and
    >> directly demonstrate that differences in the conformation
    >> of the infectious protein determine prion strain
    >> variation.
    >
    >Thank you Wyrin, that is indeed very helpful. The way I
    >would read the above is that the INFECTIVE agent is not the
    >prion particle but the scissors that cuts prions.

    Then you have clearly misread it.

    All the "strains" are the same size. There are no scissors
    (protease) involved. It is about conformations. That should
    be clear just from the abstract shown above. That is, the
    abstract above rather explicitly disproves your model.

    Key: "directly demonstrate that differences in the
    conformation of the infectious protein determine prion
    strain variation. "

    Remember, that is for yeast prions. The yeast prions sort of
    give us an existence theorem for the basics of the model. It
    is certainly allowed (and likely!) that there may be
    additional complexities with mammalian prions.

    bob
     
  8. Bob <[email protected]> wrote in message news:<[email protected]>...
    > On 18 Mar 2004 11:16:13 -0800, [email protected]
    > (Archimedes Plutonium) wrote:
    >
    > >> Nature has just published some work dealing with the
    > >> strains of prions - 'type' determined by conformation
    > >>
    > >> Conformational variations in an infectious protein
    > >> determine prion strain differences
    > >>
    > >> MOTOMASA TANAKA1, PETER CHIEN1,2, NARIMAN NABER3, ROGER
    > >> COOKE3 & JONATHAN S. WEISSMAN1,2
    > >>
    > >> A remarkable feature of prion biology is the strain
    > >> phenomenon wherein prion particles apparently composed
    > >> of the same protein lead to phenotypically distinct
    > >> transmissible states. To reconcile the existence of
    > >> strains with the 'protein-only' hypothesis of prion
    > >> transmission, it has been proposed that a single
    > >> protein can misfold into multiple distinct infectious
    > >> forms, one for each different strain. Several studies
    > >> have found correlations between strain phenotypes and
    > >> conformations of prion particles; however, whether such
    > >> differences cause or are simply a secondary
    > >> manifestation of prion strains remains unclear, largely
    > >> due to the difficulty of creating infectious material
    > >> from pure protein. Here we report a high-efficiency
    > >> protocol for infecting yeast with the [PSI+] prion
    > >> using amyloids composed of a recombinant Sup35 fragment
    > >> (Sup-NM). Using thermal stability and electron
    > >> paramagnetic resonance spectroscopy, we demonstrate
    > >> that Sup-NM amyloids formed at different temperatures
    > >> adopt distinct, stably propagating conformations.
    > >> Infection of yeast with these different amyloid
    > >> conformations leads to different [PSI+] strains. These
    > >> results establish that Sup-NM adopts an infectious
    > >> conformation before entering the cell-fulfilling a key
    > >> prediction of the prion hypothesis-and directly
    > >> demonstrate that differences in the conformation of the
    > >> infectious protein determine prion strain variation.
    > >
    > >Thank you Wyrin, that is indeed very helpful. The way I
    > >would read the above is that the INFECTIVE agent is not
    > >the prion particle but the scissors that cuts prions.
    >
    >
    > Then you have clearly misread it.
    >

    I disagree.

    > All the "strains" are the same size. There are no
    > scissors (protease) involved. It is about conformations.
    > That should be clear just from the abstract shown above.
    > That is, the abstract above rather explicitly disproves
    > your model.
    >

    The abstract above further gives supporting evidence that
    the cause of Prion disease, the cause of Alzheimers, the
    cause of Parkinsons, and perhaps the partial-cause of Liver
    Cirrhosis as rogue scissors.

    There are no rogue scissors involved with yeast. And the
    fact that yeast proteins change one anothers Conformational
    shape and form is a activity that occurs often in nature.
    What is rare and what is the cause of these diseases is a
    scissors that becomes roguish and abnormal and makes
    abnormal cuts. With an abnormal cut, the protein that
    results is somewhat immune to being cleaned up and removed
    out of the body and hence accumulates as waste.

    Once these Scissors cut the prion protein, whether they make
    Conformational shape changes amoung themselves is immaterial
    and irrelevant. They have no function or purpose and so
    shape changing one another is irrelevant.

    Bob, it was you yourself who said in a post a day or two
    ago that Prion disease infectivity has never been created
    outside the cell. The reason being is that the scissors
    that causes Prion disease has never been transered
    outside the cell.

    People that catch Mad-Cow-disease, that catch variant CJD,
    that catch Kuru; sheep that catch scrapie; cows that catch
    Mad Cow Disease, what they are all catching is a rogue
    Scissors molecule.

    Bob, scientists have found the rogue scissors for
    Alzheimers and it is APP-Scissors. But tell me, why can
    this scissors not be a communicable disease like Prion
    disease? Does the APP-Scissors unable to pass the blood
    brain barrier if eaten? Has any animal have Alzheimers
    disease other than humans? And can those animals be
    infected by transfering the scissors.

    Bob, why has no scientist found the Prion Scissors that
    causes Prion disease? Apparently the scissors for prion
    disease has a slower rate of cutting and snipping than does
    the Alzheimers scissors.

    In fact the Parkinsons scissors has the highest rate of
    production and thus disease activation. Why has no-one found
    the Parkinsons Scissors?

    And once the Parkinsons scissors is found, why is it like
    the Alzheimers Scissors in that eating the scissors is not
    communicable? Perhaps it is but then only humans get
    Alzheimers and Parkinsons and humans are rarely cannibals
    enough to have a communicable Alzheimers and a communicable
    Parkinsons.

    I wonder if the Cirrhosis of the Liver Scissors is found and
    whether the eating of that scissors transfers the disease?

    >
    > Key: "directly demonstrate that differences in the
    > conformation of the infectious protein determine prion
    > strain variation. "
    >

    Bob, please realize for decades the medical scientists have
    been worried about tau and beta-amyloid as per Alzheimers.
    For 2 decades prion scientists have been worried about
    various shape changes of the prion molecule. All of them
    were looking in the wrong place. It is irrelevant that the
    cut proteins shape change one another, or that there are a
    multitude of waste accumulating proteins. The Villian and
    Cause of these diseases is further Upstream. It is the
    Scissors that is the Disease bearing mechanism. It is the
    Scissors that is the infectious agent in Prion disease. Once
    the scissors starts cutting proteins, they are doomed to
    Accumulate. And whilst they accumulate it is irrelevant that
    they shape change one another.

    The Key , Bob, is the Scissors, everything else in Prion, in
    Alzheimers in Parkinsons , perhaps liver-cirrhosis is side
    issue irrelevant. Solve the scissors and you solve the
    disease. That is perhaps why a few drugs of the quinine or
    chlorop___ (forgotten their full names) seem to provide some
    relief to Prion victims in that they shut down the scissors
    that is propelling these diseases.

    Why is the scissors for Prion so difficult to find? Why is
    the scissors for Parkinsons so difficult to find? Could it
    be that the APP scissors of Alzheimers is one and the same
    scissors in all three of these diseases and that the APP
    scissors itself is cut down into smaller scissors?? Anyway,
    the Prion molecule and the alpha-synuclein molecule and the
    beta-amyloid molecules are all not that far different so
    that a Family Resemblance of a Scissors is invoked.

    >
    > Remember, that is for yeast prions. The yeast prions sort
    > of give us an existence theorem for the basics of the
    > model. It is certainly allowed (and likely!) that there
    > may be additional complexities with mammalian prions.
    >
    > bob

    The Yeast model is irrelevant to Prion disease.

    It behooves scientists in the Medical field of the future
    that when they run into a disease that seems to be extra-
    ordinary from all other diseases, that they thence will make
    a grave error by striking out of the mainstream of Medical
    Science in a manner that Mr. Prusiner went. Instead,
    whenever we come upon a "new disease" the most brilliant
    tactic to understand the new disease is to find the Family
    REsembling Diseases already in existence and to thence
    borrow and cross-analogize between those two diseases. Mr.
    Prusiner never helped the Prion disease with his Model, for
    it turns out that Alzheimers with its APP scissors is
    solving and conquering, along with Parkinsons and Liver-
    Cirrhosis diseases.

    The lasting theme in this Prion story, is that when you
    come upon a new disease, you are on shaky grounds by
    proffering a whole new mechanism and offering a solo
    disease category. The wise man when he encounters a new
    disease, is patiently cross examining that disease with
    existing Family of RElated Diseases.

    Strike out alone and the chances of your model being correct
    is less than 5 or 1 percent. Fit the new disease into an
    existing Family of Diseases and the chances of finding the
    correct model becomes 90 percent or better.

    Bob, we are in the homestretch of understanding Prion
    disease, and sad to say that your confidence in the
    Prusiner Model should now be extremely shakened. Bob, I
    think it is time for you to re-evaluate your beliefs in the
    Prusiner Model.

    As you said a few days ago--- scientists unable to transfer
    infectivity outside the cell. It has been 2 decades now of
    failure to do that infectivity transfer for Prion disease.
    The reason being is that the prion is not the infective
    agent but that the scissors is the infective agent.

    Archimedes Plutonium whole entire Universe is just one big
    atom where dots of the electron-dot-cloud are galaxies
     
  9. I wrote yesterday:
    >
    > Bob, scientists have found the rogue scissors for
    > Alzheimers and it is APP-Scissors. But tell me, why can
    > this scissors not be a communicable disease like Prion
    > disease? Does the APP-Scissors unable to pass the blood
    > brain barrier if eaten? Has any animal have Alzheimers
    > disease other than humans? And can those animals be
    > infected by transfering the scissors.
    >
    > Bob, why has no scientist found the Prion Scissors that
    > causes Prion disease? Apparently the scissors for prion
    > disease has a slower rate of cutting and snipping than
    > does the Alzheimers scissors.
    >
    > In fact the Parkinsons scissors has the highest rate of
    > production and thus disease activation. Why has no-one
    > found the Parkinsons Scissors?
    >

    A fascinating aspect of this is that perhaps the scissors
    that causes Alzheimers disease of the APP maybe one and the
    same scissors that causes both Prion and Parkinsons. Not
    identical APP scissors but that the body, trying to counter
    the rogueness of the APP scissors thence trys to send
    enzymes to the APP scissors to breakdown the scissors and by
    breaking it down creates a newer and also rogue scissors let
    us say APPv for "v" as in variant. And this APPv thence goes
    on to creating Parkinsons or Prion.

    Since Alzheimers is so numerous and Prion so rare and
    Parkinsons somewhat numerous but not as numerous as
    Alzheimers, that perhaps the scissors that is the infective
    agent for all three of these diseases originates from one
    rogue scissors-- the APP scissors. And that as you attempt
    to rid the body of this rogue scissors of the APP by
    marshalling enzymes to the scissors to snip it and break it
    down and carry it out of the body, that the snipping of the
    rogue APP just creates smaller roguish new scissors of
    APPv_1 and APPv_2 where one of these new smaller scissors
    causes Parkinsons and causes Prion.

    Anyway, there are alot of problems of that Model just
    outlined with facts such as that prion disease can take
    inception at a young age such as the England outbreak in the
    1990s where young people caught prion disease, but I know of
    no Alzheimers of young people. And it seems as though
    Parkinsons is caught at a younger age than is Alzheimers. So
    there seems to be a incongruence of age of catching if the
    APP scissors of Alzheimers is to blame. But perhaps that
    discrepancy is easily handled. Another discrepancy is that
    it appears Prion disease is widespread in very many animal
    species but that Alzheimers and Parkinsons is confined to
    humans. But that discrepancy may also be easily overcome.

    Anyway, what is the state of research as to a scissors that
    cuts proteins and whether the prion proteins have a specific
    individualized scissors and whether Parkinsons has a
    specific scissors for its alpha-synuclein or whether the
    Alzheimers APP scissors is involved with prions and alpha-
    synuclein.

    ARchimedes Plutonium whole entire Universe is just one big
    atom where dots of the electron-dot-cloud are galaxies
     
  10. Bob

    Bob Guest

    On 19 Mar 2004 09:56:47 -0800, [email protected] (Archimedes
    Plutonium) wrote:

    >Bob <[email protected]> wrote in message
    >news:<[email protected]>...
    >> On 18 Mar 2004 11:16:13 -0800, [email protected]
    >> (Archimedes Plutonium) wrote:
    >>
    >> >> Nature has just published some work dealing with the
    >> >> strains of prions - 'type' determined by conformation
    >> >>
    >> >> Conformational variations in an infectious protein
    >> >> determine prion strain differences
    >> >>
    >> >> MOTOMASA TANAKA1, PETER CHIEN1,2, NARIMAN NABER3,
    >> >> ROGER COOKE3 & JONATHAN S. WEISSMAN1,2
    >> >>
    >> >> A remarkable feature of prion biology is the strain
    >> >> phenomenon wherein prion particles apparently composed
    >> >> of the same protein lead to phenotypically distinct
    >> >> transmissible states. To reconcile the existence of
    >> >> strains with the 'protein-only' hypothesis of prion
    >> >> transmission, it has been proposed that a single
    >> >> protein can misfold into multiple distinct infectious
    >> >> forms, one for each different strain. Several studies
    >> >> have found correlations between strain phenotypes and
    >> >> conformations of prion particles; however, whether
    >> >> such differences cause or are simply a secondary
    >> >> manifestation of prion strains remains unclear,
    >> >> largely due to the difficulty of creating infectious
    >> >> material from pure protein. Here we report a high-
    >> >> efficiency protocol for infecting yeast with the
    >> >> [PSI+] prion using amyloids composed of a recombinant
    >> >> Sup35 fragment (Sup-NM). Using thermal stability and
    >> >> electron paramagnetic resonance spectroscopy, we
    >> >> demonstrate that Sup-NM amyloids formed at different
    >> >> temperatures adopt distinct, stably propagating
    >> >> conformations. Infection of yeast with these different
    >> >> amyloid conformations leads to different [PSI+]
    >> >> strains. These results establish that Sup-NM adopts an
    >> >> infectious conformation before entering the cell-
    >> >> fulfilling a key prediction of the prion hypothesis-
    >> >> and directly demonstrate that differences in the
    >> >> conformation of the infectious protein determine prion
    >> >> strain variation.
    >> >
    >> >Thank you Wyrin, that is indeed very helpful. The way I
    >> >would read the above is that the INFECTIVE agent is not
    >> >the prion particle but the scissors that cuts prions.
    >>
    >>
    >> Then you have clearly misread it.
    >>
    >
    >I disagree.
    >
    >
    >
    >> All the "strains" are the same size. There are no
    >> scissors (protease) involved. It is about conformations.
    >> That should be clear just from the abstract shown above.
    >> That is, the abstract above rather explicitly disproves
    >> your model.
    >>
    >
    >The abstract above further gives supporting evidence that
    >the cause of Prion disease, the cause of Alzheimers, the
    >cause of Parkinsons, and perhaps the partial-cause of Liver
    >Cirrhosis as rogue scissors.

    The abstract above is about yeast. It cannot possibly say
    anything about any special properties of mammalian prions
    (beyond properties of yeast prions). It says, quite
    explicitly, that yeast prions can take on many conformations
    with different properties -- exactly what the traditional
    model proposes.

    >
    >Bob, scientists have found the rogue scissors for
    >Alzheimers and it is APP-Scissors. But tell me, why
    >can this scissors not be a communicable disease like
    >Prion disease?

    Well, infectivity is really a somewhat separate issue. It is
    quite odd that any protein is infectious in any sense. Most
    proteins get digested in your gut, and do not enter the
    body. (I have read something about how some proteins might
    get incorporated without being digested. I don't remember
    any detail.) That the PrSc does avoid digestion (at least to
    some extent, and I suspect it is only partial, maybe even
    slight) is probably due to its compact, insoluble nature.

    (The Alz proteases are membrane bound enzymes. The idea that
    a protease would be taken up and get incorporated into
    membranes is even more mind boggling, though presumably not
    impossible.)

    Remember that infectiousness is only one part of the prion
    story. Many cases of prion disease have nothing to do with
    infection at all. Genetic cases are known, in all cases
    documented, to be due to a mutation in the Pr gene
    (presumably making it more likely that the resulting protein
    will switch to the Sc conformation.)

    Of course, the infectiousness is what caught the attention
    of many -- since the infectious agent seemed so different
    from any other known infectious agent. Now that we
    understand that the apparent infectious agent is an altered
    cell protein, that part is solved. If we had not known of
    the infectiousness, the other types of prion diseases would
    simply be lumped with the other neurodegenerative diseases.

    We can make many models within the broad umbrella of an
    altered cellular protein which behaves as infectious. I
    suppose we could even make such a model for a protease
    (scissors). But why do so, with no evidence for it, and
    simpler models will do? And how do you propose that the
    protease makes more of itself?

    >Does the APP-Scissors unable to pass the blood brain
    >barrier if eaten? Has any animal have Alzheimers disease
    >other than humans?

    only experimental systems with mice, i think

    >And can those animals be infected by transfering the
    >scissors.

    Well, certainly not by feeding the protease.

    I have not been paying much attention to this mouse work.

    >
    >Bob, why has no scientist found the Prion Scissors that
    >causes Prion disease?

    Maybe there is no such enzyme. And since we know that the
    normal and Sc forms are the same size, then we know there is
    no such enzyme.

    >
    >And once the Parkinsons scissors is found, why is it like
    >the Alzheimers Scissors in that eating the scissors is not
    >communicable?

    As noted, the infectiousness of any proteins will be very
    rare, and certainly is not a fundamental property of the
    disease (including of prion diseases).

    >
    >Bob, please realize for decades the medical scientists have
    >been worried about tau and beta-amyloid as per Alzheimers.
    >For 2 decades prion scientists have been worried about
    >various shape changes of the prion molecule. All of them
    >were looking in the wrong place. It is irrelevant that the
    >cut proteins shape change one another, or that there are a
    >multitude of waste accumulating proteins. The Villian and
    >Cause of these diseases is further Upstream. It is the
    >Scissors that is the Disease bearing mechanism.

    Take Alz as an example. A cuts B, and B is toxic. Then, both
    A and B are part of the cause. But B is most fundamentally
    the cause. A (the protease) may be one way of creating the
    toxic protein B in this case. But there may be (and are)
    other ways to make B. As noted elsewhere, all mutations
    known to promote prion diseases are in the Sc gene.

    bob
     
  11. Bob <[email protected]> wrote in message news:<[email protected]>...
    > On 19 Mar 2004 09:56:47 -0800, [email protected]
    > (Archimedes Plutonium) wrote:
    (snipped)

    > >
    > >Bob, scientists have found the rogue scissors for
    > >Alzheimers and it is APP-Scissors. But tell me, why can
    > >this scissors not be a communicable disease like Prion
    > >disease?
    >
    > Well, infectivity is really a somewhat separate issue. It
    > is quite odd that any protein is infectious in any sense.
    > Most proteins get digested in your gut, and do not enter
    > the body. (I have read something about how some proteins
    > might get incorporated without being digested. I don't
    > remember any detail.) That the PrSc does avoid digestion
    > (at least to some extent, and I suspect it is only
    > partial, maybe even slight) is probably due to its
    > compact, insoluble nature.
    >
    > (The Alz proteases are membrane bound enzymes. The idea
    > that a protease would be taken up and get incorporated
    > into membranes is even more mind boggling, though
    > presumably not impossible.)
    >
    >
    > Remember that infectiousness is only one part of the prion
    > story. Many cases of prion disease have nothing to do with
    > infection at all. Genetic cases are known, in all cases
    > documented, to be due to a mutation in the Pr gene
    > (presumably making it more likely that the resulting
    > protein will switch to the Sc conformation.)
    >
    >
    > Of course, the infectiousness is what caught the attention
    > of many -- since the infectious agent seemed so different
    > from any other known infectious agent. Now that we
    > understand that the apparent infectious agent is an
    > altered cell protein, that part is solved. If we had not
    > known of the infectiousness, the other types of prion
    > diseases would simply be lumped with the other
    > neurodegenerative diseases.
    >
    > We can make many models within the broad umbrella of an
    > altered cellular protein which behaves as infectious. I
    > suppose we could even make such a model for a protease
    > (scissors). But why do so, with no evidence for it, and
    > simpler models will do? And how do you propose that the
    > protease makes more of itself?
    >
    >
    > >Does the APP-Scissors unable to pass the blood brain
    > >barrier if eaten? Has any animal have Alzheimers disease
    > >other than humans?
    >
    > only experimental systems with mice, i think
    >
    >
    > >And can those animals be infected by transfering the
    > >scissors.
    >
    >
    > Well, certainly not by feeding the protease.
    >
    > I have not been paying much attention to this mouse work.
    >
    >
    > >
    > >Bob, why has no scientist found the Prion Scissors that
    > >causes Prion disease?
    >
    > Maybe there is no such enzyme. And since we know that the
    > normal and Sc forms are the same size, then we know there
    > is no such enzyme.
    >

    Bob, how well known is the upstream manufacturing of good
    prions? Do scientist know in detail how the good prion is
    created? And once created, how it is transported to the site
    where it is to function and do its job, whatever that maybe?
    Is the creation of good prions well mapped out?

    I do not know the relative size of Sc prions compared to beta-
    amyloid and compared to alpha-synuclein.

    >
    > >
    > >And once the Parkinsons scissors is found, why is it like
    > >the Alzheimers Scissors in that eating the scissors is
    > >not communicable?
    >
    > As noted, the infectiousness of any proteins will be very
    > rare, and certainly is not a fundamental property of the
    > disease (including of prion diseases).
    >
    >
    > >
    > >Bob, please realize for decades the medical scientists
    > >have been worried about tau and beta-amyloid as per
    > >Alzheimers. For 2 decades prion scientists have been
    > >worried about various shape changes of the prion
    > >molecule. All of them were looking in the wrong place. It
    > >is irrelevant that the cut proteins shape change one
    > >another, or that there are a multitude of waste
    > >accumulating proteins. The Villian and Cause of these
    > >diseases is further Upstream. It is the Scissors that is
    > >the Disease bearing mechanism.
    >
    >
    > Take Alz as an example. A cuts B, and B is toxic. Then,
    > both A and B are part of the cause. But B is most
    > fundamentally the cause. A (the protease) may be one way
    > of creating the toxic protein B in this case. But there
    > may be (and are) other ways to make B. As noted elsewhere,
    > all mutations known to promote prion diseases are in the
    > Sc gene.
    >
    >
    > bob

    Bob, about infectivity. I suppose most activity is governed
    by shapes of molecules. I am guessing that the hydrogen-
    bonds are the most often largest determinants of the shape
    of a protein, perhaps even viruses. Can we say the
    difference between bad prions and good prions is the
    difference of an X number of hydrogen bonds?

    Three Models for Prion diseases:
    (1) Prusiner Model where proteins alter other proteins
    (2) rogue Scissors Model where scissors corrupt good prions
    into bad ones
    (3) manufacturing-site of prions gets corrupted and then
    churns out bad prions

    Alzheimers would fit (2) where a scissors creates beta-
    amyloid. I guess in Alzheimers neither beta-amyloid or tau
    are produced further upstream of Manufacturing Site.

    Parkinsons is probably (3) Manufacturing Site of alpha-
    synuclein

    Since no scissors has ever been found for prion, I favor (3)
    that a corrupting of the Manufacturing Site of good prions.
    Perhaps a bad prion can alter the Manufacturing Site. This
    would differ from the Prusiner Model in that his model has
    bad prions directly altering good prions. My model would
    have the bad prion alter the manufacturing-site (the cookie
    cutter) which then spews out bad prions.

    I wonder if the hydrogen bond is the key to infectivity? I
    wonder if viruses enter cells due to their hydrogen-bonds
    allows them to enter. If hydrogen-bonds is the most
    elemental level of understanding infectivity, then I
    wonder if the hydrogen bonds of bad prions is related to
    any viral-hydrogen-bonds.

    Bob, is there any virus that is as immune to protease
    breakdown as is the prion protein molecule?

    When dealing with these 3 diseases I often wonder whether
    the disease is a weakness in protein structure that bad
    proteins are produced or whether the disease is more of a
    aspect that the body cannot get rid of the protein. So that
    50 percent of these diseases is the production of bad
    proteins but the other 50% is the inability of the body to
    get rid of the accumulated plaques. So we can fault a
    neighborhood for creating and generating too much garbage or
    fault the trash collection people for lack of removing. And
    I feel we spend too much time on only 50% of theses diseases
    in how they are created and not enough time spent on whether
    the body can be made more waste removal efficient.

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

    >
    > >Does the APP-Scissors unable to pass the blood brain
    > >barrier if eaten? Has any animal have Alzheimers disease
    > >other than humans?
    >
    > only experimental systems with mice, i think
    >

    Bob, any experiments on mice where they are normal and where
    a number of APP scissors is placed into the mouse brain and
    whether they contract Alzheimers?

    I take it you want a vacation from posting to this subject,
    and I am in the opposite mood of wanting more answers.

    Archimedes Plutonium whole entire Universe is just one big
    atom where dots of the electron-dot-cloud are galaxies
     
  13. Bob

    Bob Guest

    On 20 Mar 2004 23:48:01 -0800, [email protected] (Archimedes
    Plutonium) wrote:

    >
    >Bob, how well known is the upstream manufacturing of good
    >prions? Do scientist know in detail how the good prion is
    >created? And once created, how it is transported to the
    >site where it is to function and do its job, whatever that
    >maybe? Is the creation of good prions well mapped out?
    >

    In general terms, but it is always complex for membrane
    proteins. In fact, this may be an important issue. It may
    be that the normal protein is most susceptible to
    conversion during its maturation, and less susceptible once
    fully formed.

    Note that a conversion can be carried out in vitro with
    mammalian prions. It is just that the product is not
    infectious. Thus the notion of conversion is solid enough,
    but the precise process of relevant conversion may have more
    to the story.

    >
    >Bob, about infectivity. I suppose most activity is governed
    >by shapes of molecules. I am guessing that the hydrogen-
    >bonds are the most often largest determinants of the shape
    >of a protein, perhaps even viruses. Can we say the
    >difference between bad prions and good prions is the
    >difference of an X number of hydrogen bonds?

    protein structures are determined by a range of so called
    weak bonds, including H-bonds. No point is served by trying
    to focus on one type alone.

    >
    >Three Models for Prion diseases:
    >(1) Prusiner Model where proteins alter other proteins
    >(2) rogue Scissors Model where scissors corrupt good prions
    > into bad ones
    >(3) manufacturing-site of prions gets corrupted and then
    > churns out bad prions
    >
    >Alzheimers would fit (2) where a scissors creates beta-
    >amyloid. I guess in Alzheimers neither beta-amyloid or tau
    >are produced further upstream of Manufacturing Site.
    >
    >Parkinsons is probably (3) Manufacturing Site of alpha-
    >synuclein
    >
    >Since no scissors has ever been found for prion, I favor
    >(3) that a corrupting of the Manufacturing Site of good
    >prions. Perhaps a bad prion can alter the Manufacturing
    >Site. This would differ from the Prusiner Model in that his
    >model has bad prions directly altering good prions. My
    >model would have the bad prion alter the manufacturing-site
    >(the cookie cutter) which then spews out bad prions.

    As I read that, those two models are almost variations on
    one theme -- maybe one or another extreme. That is, the
    agent causes the normal protein to change. I am sure
    people would be delighted to find any variation there that
    really worked.

    But remember, prion conversion is well demonstrated, and
    in yeast in vitro conversion produces biologically
    relevant product. So there is no logical need for anything
    more, but nature often does not do things the simple way
    we would like.

    >
    >When dealing with these 3 diseases I often wonder whether
    >the disease is a weakness in protein structure that bad
    >proteins are produced or whether the disease is more of a
    >aspect that the body cannot get rid of the protein. So that
    >50 percent of these diseases is the production of bad
    >proteins but the other 50% is the inability of the body to
    >get rid of the accumulated plaques. So we can fault a
    >neighborhood for creating and generating too much garbage
    >or fault the trash collection people for lack of removing.
    >And I feel we spend too much time on only 50% of theses
    >diseases in how they are created and not enough time spent
    >on whether the body can be made more waste removal
    >efficient.

    As you point out, those are not mutually exclusive. Much
    attention is being directed to protein degradation. And it
    is beginning to be recognized that overwhelming the
    degradation machinery is undoubtedly bad.

    bob
     
  14. Bob

    Bob Guest

    On 21 Mar 2004 22:07:02 -0800, [email protected] (Archimedes
    Plutonium) wrote:

    >Bob <[email protected]> wrote in message
    >news:<[email protected]>...
    >
    >>
    >> >Does the APP-Scissors unable to pass the blood brain
    >> >barrier if eaten? Has any animal have Alzheimers disease
    >> >other than humans?
    >>
    >> only experimental systems with mice, i think
    >>
    >
    >Bob, any experiments on mice where they are normal and
    >where a number of APP scissors is placed into the mouse
    >brain and whether they contract Alzheimers?
    >

    no idea. But it is mind boggling to think it would work.
    Getting the protease properly inserted into the membrane
    would be remarkable. (That doesn't mean it shouldn't be
    tried, but ...)

    >I take it you want a vacation from posting to this subject,

    I don't think I exactly said that. But I did say that there
    are areas where we should sit back and wait for results. For
    those who are not working in a field to speculate much on
    how it will proceed is not too fruitful.

    Given the usual pace in this field, this will give s plenty
    of time to do other things.

    bob
     
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