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From: TSS ()
Subject: Concerns with cross-species prion infection
Date: April 7, 2005 at 7:14 pm PST

-------- Original Message --------
Subject: Concerns with cross-species prion infection
Date: Thu, 07 Apr 2005 21:20:39 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy

Concerns with cross-species prion infection

New research on prions, the infectious proteins behind "mad cow" disease
and Creutzfeld-Jakob disease in humans, suggests that the ability of
prions in one species to infect other species depends on the shape of
the toxic threadlike fibers produced by the prion. Two studies on the
topic appear in the 8 April issue of the journal Cell.

Although research suggests that prions from one species rarely infect
other species, some scientists believe the species barrier was breached
when a new version of Creutzfeld-Jakob disease appeared in humans after
several recent epidemics of bovine spongiform encephalopathy or "mad
cow" disease. Since then, barriers to the transmission of prion diseases
between species "have emerged as a major public health issue," according
to Eric Jones and Witold Surewicz of Case Western Reserve University.

Prion diseases are caused by misfolded variants of the normal prion
protein, which aggregate into fibrous tangles called amyloid fibrils and
cause fatal wasting of brain tissue. The abnormally folded protein
itself appears to act as an infectious agent, transmitting disease
without a DNA or RNA genome such as in a virus. Although disease prions
seem to infect normal prions by binding to them and forcing them to take
on the abnormal configuration, researchers remain uncertain about the
exact molecular details of infection.

Earlier studies identified many "strains" of disease prions across
mammalian and yeast species. Researchers thought these strains could be
defined by differences in the underlying amino acid sequences of the
prions. Under this scenario, disease transmission would be more likely
between species with similar prion amino acid sequences.

But a few mysteries stood in the way. Some individuals harbored several
different prion strains that caused different disease outcomes, even
though all the prions shared the same amino acid sequence. In some
cases, a single amino acid change in one species could completely change
its ability to infect a previously "off-limits" species, Surewicz and
colleagues found.

In a study published last year in the journal Molecular Cell, Surewuicz
and colleagues also demonstrated that a "preseeding" process between
animals with different prion amino acid sequences could overcome species
barriers. For instance, mouse prion fibrils normally infect humans but
not hamsters. But when mouse prions were brought into contact with
hamster prion amyloid fibrils, a new strain of mouse fibrils emerged
with the ability to infect hamsters but not humans. The new mouse strain
had the same amino acid sequence as the original mouse strain but
completely different infectious capabilities.

With the help of atomic-level microscopic observation of prions in
humans, mice, and hamsters, Jones and Surewicz discovered that it is the
specific shape of the amyloid fibrils, and not the amino acid sequences,
that may allow prions from one species to infect another.

In a second Cell study, Jonathan Weissman and colleagues at the
University of California, San Francisco came to the same conclusion in
their experiments with yeast. They too discovered that the particular
shape of a prion amyloid fibril was the determining factor in whether
one species of yeast could infect another yeast species.

Just as in the case with the preseeded mice fibrils, a particular fibril
shape in Saccharomyces cerevisiae yeast allowed prion transmission to
Candida albicans yeast. The transmission event led to a new strain of
Candida prion fibrils that could in turn infect Saccharomyces.

Although fibril shape appears to be the deciding infective factor, amino
acid sequence is still important because it defines a set of possible
preferred fibril shapes that prions can adopt, Weissman says. Species
with similar amino acids sequences share an overlapping set of shapes,
which helps explain why species with shared sequences have the ability
to infect each other.

Surewicz says the next step in their research will be to examine fibril
shape differences at much higher resolution. Their experiments also used
a shortened version of the mammalian prion protein, so they hope to test
the fibril factor in a full-length protein soon.

Jones and Surewicz also note that the new findings offer "the unsettling
possibility" that repeated cross-species transmission events might
eventually create prion fibril strains that can bridge the infection gap
between previously separate animals like humans and elk and deer, which
suffer from a prion disease called chronic wasting disease.

Surewicz stresses, however, prion infection between species is still
rare. "Fortunately, transmission by eating is very ineffective. There
have been hundreds of thousands of bovine spongiform encephalopathy
cases, for example, and lots of people exposed to tainted beef products,
but very few cases of variant Creutzfeld-Jakob."

He says there "must be protective mechanisms working there, but we don't
know what they are."

Reviewed: April 07, 2005
Rick Nauert PhD


Copyright: ©Cell Press

Mechanism of Cross-Species Prion Transmission: An Infectious
Conformation Compatible with Two Highly Divergent Yeast Prion Proteins

M. Tanaka, P. Chien, K. Yonekura, and J.S. Weissman

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"" claiming to be

Fibril Conformation as the Basis of Species-and Strain-Dependent Seeding
Specificity of Mammalian Prion Amyloids

E.M. Jones and W.K. Surewicz

Transmissible spongiform encephalopathies (TSE) are caused by
unconventional infectious agents called prions, believed to be misfolded
proteins that can induce the misfolding of cellular counterparts. The
ability of a prion to infect proteins from other species depends on the
particular prion strain present and decreases as the primary sequences
of the affected proteins diverge. However, the molecular basis for this
species barrier remains enigmatic. Two papers in this issue, from
Tanaka, Jones, and their colleagues, examine prion transmission in yeast
and mammalian cells and provide strong evidence that distinct
conformations of prion amyloid fibrils underlie the existence of
different prion strains. These papers establish that strain conformation
is the critical determinant of cross-species prion transmission and
suggest that the primary sequence affects transmission by altering the
spectrum of preferred prion conformations.

The Biological and Chemical Basis for Tissue-Selective Amyloid Disease

Y. Sekijima, R.L. Wiseman, J. Matteson, P. Hammarström, S.R. Miller,
A.R. Sawkar, W.E. Balch, and J.W. Kelly

Numerous diseases, including Alzheimer's disease, involve formation of
extracellular aggregates or amyloids of secreted mutant proteins.
Amyloid formation is limited by ER-associated degradation (ERAD), which
should dispose of misfolded mutant proteins before they are secreted.
Here, Sekijima et al. demonstrate that disease-associated protein
variants are secreted with wild-type efficiency in spite of compromised
folding energetics. Only the most highly destabilized variants are
subjected to ERAD and then only in certain tissues, providing insight
into tissue-selective amyloidosis.



Proof Mad Cow Is The Same As Alzheimer's And CJD

... From: TSS; Subject: CJD or Alzheimer's, THE PA STUDY...full text;
Date: May
7, 2001 at 10:24 am PST; Diagnosis of dementia: Clinicopathologic ...


More Evidence Mad Cow Same As CJD And Alzheimer's

... From: TSS ( Subject: CJD or
Alzheimer's, THE
PA STUDY...full text Date: May 7, 2001 at 10:24 am PST ...



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