[1]
Date: Fri, 12 Jan 2001 11:39:30 -0500
From: Hopkins, Andrew S. <amh7@cdc.gov>
A Short Comment on the Properties of Prions
-------------------------------------------
[The previous posting in this series, CJD (new var.) - UK: some questions
(03), contained some misstatements regarding the nature of prions. Dr.
Hopkins sets the record straight.]
Prions do not really act directly on the "quaternary" forms of a protein
although they theoretically could affect it indirectly. The quaternary form
of a protein refers to assemblies of multiple polypeptide chains such as the
four chains of hemoglobin. Most of the time the author seems to be talking
about single chain proteins anyway. The folded shape of a protein is its
tertiary structure. Prions, according to the present literature, arise due
to some kind of autocatalytic aberrant beta-sheet formation, which is a
secondary structure property, which may in turn affect tertiary folding.
Susan Liebman's work on the Psi factor in _Saccharomyces cerevisiae_ (a
"Yeast" prion) shows that over-expression of heat shock proteins, can
overcome the Psi phenotype, presumably by refolding the protein to its
correct form. Other than the human PrP protein and its homologue in other
species and the _S. cerevisiae_ example, I don't believe the literature is
replete with large numbers of examples of other proteins which exhibit prion
type autocatalytic misfolding being: quote "discovered across families and
even phyla" as this author states.
In the second paragraph the author discusses chaperonins directing
alternative folding pathways leading to "crystalline" forms of a protein.
Thus the author seems to be under the misimpression that "prions" are
crystalline forms of a protein. This is certainly not true. If it were, the
3-dimensional structure of the human prion protein with approximately 260
amino acids
would have been solved in an afternoon. Prions are not crystalline. They are
insoluble amorphous tangles which cannot be crystallized under normal
conditions because they are completely insoluble in any of the solutions
used to generate crystals for X-ray analysis.
Third paragraph refers to "ubiquitin-resistance." No such thing. Ubiquitin
does not do anything directly to proteins itself. It just targets them for
pathways towards proteolytic degradation. Ubiquitin itself is not a
protease, and does not degrade proteins. See:
<http://jcsmr.anu.edu.au/dmm/molgen/ubiquitin%20laboratory/ubiquitin_lab_hom
e page.htm>
The last paragraph refers to prions as "chaperonins." There is no evidence
for this, and the author did not propose it previously, so where did this
hypothesis come from?
--
Andy Hopkins
CDC
<amh7@cdc.gov>
******
[2]
Date: Sat, 13 Jan 2001 10:02:27 +0000
From: O. Hotz de Baar <Oz@upthorpe.demon.co.uk>
Further Comment on the Analysis of Outbreak Data
------------------------------------------------
I have had some further thoughts on the original posting that commented on
the possibility of misreported variant CJD cases possibly associated with
triggering of susceptible genotypes (e.g. familial/GSS) on exposure to
infective prions (e.g. BSE).
There is enough circumstantial evidence on possible prionic triggering of
susceptible individuals to consider this a possible scenario [in my
opinion]. Note that
Robert LaBudde made this comment some years ago, in particular commenting on
the smoothness of the (variant CJD+GSS) curve compared to the variant CJD
one and speculating on this. I do not know if GSS has been strain typed.
The data has to be based on dates of deaths as there are no other data. It
is unfortunate that a good baseline for sporadic cases is probably not
available, and as even referrals are not given pre-1990 it is not easy to
disentangle the effect of improved reporting. Inevitably any evaluation will
be crude in the extreme, with only the UK dates of death from the UK CJD
site that can be used for comparison. In particular these are subject to
varying delays as those affected can be kept alive for between months and
years. It is a truly tragic disease. For convenience, and for further
discussion, I offer the following sets of data. The first table can be
conveniently viewed as a table if you set your display font as a monopitched
font (e.g.g courier), the second block is comma delimited for cut & paste
into a spreadsheet.
Personally I don't see any real evidence for a peak although one might argue
weakly that the increase seen in the curves based on dates of onset show a
greater increase that might be warranted if you believe there may have been
some 'effective mis-reporting'.
A = Total of all UK CJD
B = Total less iatrogenic (which by definition is a known infective source)
C = variant CJD+GSS
D = variant CJD+GSS+familial
Year A B C D
1985 28 27 0 1
1986 26 26 0 0
1987 24 24 1 1
1988 24 23 0 1
1989 32 30 0 2
1990 33 28 0 0
1991 36 35 0 3
1992 51 49 1 6
1993 46 42 2 4
1994 59 58 3 7
1995 47 43 6 8
1996 60 56 14 16
1997 80 74 11 15
1998 89 86 19 23
1999 84 78 15 17
2000 72 65 25 27
--
O. Hotz de Baar
<Oz@upthorpe.demon.co.uk>
[Some interesting thoughts and discussion have been generated by this series
of postings. This seems an appropriate juncture to cut this thread until such
time as new data becomes av
A ProMED-mail post
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