----- Original Message -----
Sent: Saturday, December 27, 2003 11:16
PM
Subject: Re: Prion research and mad cow
disease
Well, I think
I have to amend my remarks. After reading a bit more of Prusiner's
work I think I seriously mis-stated when I said that "prion" does
not only refer to "misfolded" version of certain proteins. I was getting
confused in his usage of the two terms 'prion' and 'prion protein'.
:(
'Prion' is
more like a term referring mostly to function: to what a certain 'some
thing' does. 'PrPSc' refers to the specific physical entity which
comprises the 'some thing'.
So, it appears
that Prusiner uses the term 'prion' to refer only to
the pathological entity that is composed of
the "misfolded" version of a PrP.
(from: "Prions
in Skeletal Muscles", 2002)
Prions
cause neurodegenerative diseases, including Creutzfeldt-Jakob disease
(CJD), bovine spongiform encephalopathy (BSE), chronic wasting
disease (CWD), and scrapie in mammals (1).
The only known constituent of the infectious prion is an
aberrant isoform (PrPSc) of the normal cellular
(PrPC) prion protein (PrP). PrPC is a cell-surface
glycoprotein, the _expression_ of which is necessary for the
production of prions (2, 3). In
animals with clinical signs of scrapie, the highest levels of
prions are found in the brain and spinal cord, but other
tissues, particularly those of the reticuloendothelial system,
exhibit substantial prion titers
Also,
from his UCSF website:
Nascent
prions are created either spontaneously by mutation of a host protein or
by exposure to an exogenous source. Prions are composed largely, if not
entirely, of a modified form of the prion protein (PrP) designated PrPSc.
Like other infectious pathogens, they multiply but prions do not have a
nucleic acid genome to direct the synthesis of their progeny. A
post-translational, conformational change features in the conversion of
cellular PrP (PrPC) into PrPSc during which alpha-helices are transformed
into beta-sheets. Since this structural transition in PrP underlies both
the replication of prions and the pathogenesis of CNS degeneration, much
of the effort in the laboratory is devoted to elucidating the molecular
events responsible for this process. Indeed, prion diseases seem to be
disorders of protein conformation.
So, this
changes several of my remarks as follows:
This is just
plain wrong:
So,
when talking about a prion-caused disease, we should
probably not say that "the prion causes x", but rather something
like: "PrPSc causes x" or "the pathological isoform of PrP causes x".
Otherwise, we would be saying something analogous to "genes cause x" when
we really mean that "mutated genes cause x".
This is also largely
wrong:
When is a protein a
prion?
The
answer to this is still a bit unclear to me. I speculate from what I read
that a protein can be a called a prion based not necessarily on
specific amino acid sequence (which varies with species), but on some
(mostly) functional criteria:
1) if
a protein is coded for in the genome of the species under
study
2)
and if it can be folded into the two isoforms representing PrPC
and PrPSc
3)
and if the PrPC isoform is normally occurring and functional in the
species under study
4) and if the PrPSc isoform is not
functional in that species
5)
and if the PrPSc isoform can convert the PrPC in the organism into
PrPSc
6)
and if the PrPSc isoform is highly resistant to destruction by
proteasomes.
Hi
JohnM,
I was a bit
hazy on what 'prion' exactly referred to myself. Here's what I've dug
up.
Prion - short
for "proteinaceous infectious particle", specifically ones that lacks
nucleic acid (see quote below). The term was coined by Stanley Prusiner at
Univ. of Cal. Med School in 1982. Prions are proteins and contain no
RNA or DNA. he won a Nobel Price for his work on prions in 1997.
PrP - short for "prion protein".
From what I
read, neither "prion" nor "PrP" automatically imply that
they refer only to the "misfolded" version of
the proteins. However, many websites talk about prions
as if the term 'prion' did refer only to the "misfolded" versions. Those
sites appear to me to be incorrect.
Prusiner's
Nobel lecture (in PDF form):
Prusiner's paper in "Science" (1997, No. 5336,
Oct., p. 245-251) is available free at:
In the
Science paper, footnote 1 is as follows:
Prions are defined as proteinaceous
infectious particles that lack nucleic acid. PrPC is the
cellular prion protein; PrPSc is the pathologic isoform.
Amino-terminal truncation during limited proteolysis of PrPSc
produces PrP 27-30 (so named because this protease-resistant core of
PrPSc migrates at ~27 to 30 kD).
Further on
in the paper:
PrPSc is the major, and
very probably the only, component of the infectious prion particle.
PrPSc formation is a posttranslational process involving only
a conformational change in PrPC
So,
when talking about a prion-caused disease, we should
probably not say that "the prion causes x", but rather something
like: "PrPSc causes x" or "the pathological isoform of PrP causes x".
Otherwise, we would be saying something analogous to "genes cause x" when
we really mean that "mutated genes cause x".
I am
uncertain if all currently identified pathological isoforms of
prions are termed "PrPSc", or if there are other terms (for pathological
isoforms of PrP found in some other species, for example), but I believe
it does refer to all forms, even though the "Sc" in "PrPSc" apparently
initially was a reference to scrapie (the sheep version of BSE). >From the
Nobel lecture:
"The amino acid sequence of PrPSc
corresponds to that encoded by the PrP gene of the mammalian host in
which it last replicated. In constrast to pathogens with a nucleinc-acid
genome that encodes strain-specific properties in genes, prions encipher
these properties in the tertiary structure of PrPSc." (p.
4)
When is a
protein a prion?
The answer
to this is still a bit unclear to me. I speculate from what I read
that a protein can be a called a prion based not necessarily on
specific amino acid sequence (which varies with species), but on some
(mostly) functional criteria:
1) if a
protein is coded for in the genome of the species under
study
2) and if it
can be folded into the two isoforms representing PrPC and
PrPSc
3) and if
the PrPC isoform is normally occurring and functional in the species
under study
4) and if the PrPSc isoform is not functional in
that species
5) and if
the PrPSc isoform can convert the PrPC in the organism into
PrPSc
6) and if
the PrPSc isoform is highly resistant to destruction by
proteasomes.
Other "what
is a prion?" sites:
Regards,
Tim
Tim and All,
I told several times that I am a
virgin-minded layman (=stupid) in the biology-related sciences up from
the macromolecules. Question:
in superficial reading I got the
impression that "PRION" is used as the specific villain in mad cow
disease. I thought it is a 'small' piece of proteinatious molecule with
an inorderly folding. Maybe the latter is pertinent to MCD only and
prions can be 'orderly folded protein
midgets' with RNA only, as well? Many
other animals (fish, etc.) have prions, do they spread mad fish disease?
I don't think so.
I find it unreasonable to 'wait 30
months' or any, since infected remnants (mentioned are: placentas)
of MCD cows stay for years in pastures ready to infect deer,
hare etc, which then do the favor for the coyotes, wolves, people
and other predators. That is pertinent to PA, NJ, NY, MN, and all other
states as well, not only the West.
Agribiz - as any other successful biz
does not care beyond making money today. That's why that stupid law was
concocted in the US.
Suicidal behavior? for the others. Not
for "me". The government owning oligarchy will feed safely on their
private (organic) sources of their food staple, even if millions fall
over like mad cows.
Protein folding is big deal. I made
experiments myself (El Micr.-ly controlled) "straightening out" protein
(and the like) molecules, froze them in unfolded state, then restored
the mobility and it reformed the orig. folding perfectly, no matter in
what 'changed' environment. So a "misfolding" is more than an esthetic
nuisance.
It forms the joining sites (or hides
them) for enzymes, etc., so the conformation is a fundamental adage to
the "life processes".
I asked the question in the 1st par
because it seems that we have mixed info and I don't have the time to
study along books on the proteinatious materials of recent. The old ones
I know do not include the word prion. Just as the recent ones do not
include words which will be coined in the future, when we (hopefully)
will learn more about nature. We can use more knowledge.
I hope the US science will come up with
a better SAFE solution than cremating 45million cows (and bulls!). It's
a mad mad world.
John M