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- WASHINGTON (Reuters) - Prions,
the distorted proteins blamed for causing mad cow disease and related fatal
brain illnesses, can cause disease all by themselves, researchers said
on Thursday.
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- A team at the University of California San Francisco
said they had shown that it was indeed prions, and not some other unknown
molecule, that caused the brain-destroying infections.
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- Prions have mystified scientists since they were discovered.
Normally present in the brain and other tissue, they can take on an abnormally
folded form that causes the brain to become spongy and, eventually, to
wither.
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- They can replicate, clump up and cause disease without
the use of any kind of genetic material at all, unlike viruses, bacteria,
and parasites.
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- Prions survive cooking at high heat for long times and
only a few chemicals are known to destroy them.
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- They are blamed for a range of diseases known as transmissible
spongiform encephalopathies (TSEs), including mad cow disease, scrapie
in sheep, Creutzfeldt Jakob disease (CJD) in humans, and a new kind of
CJD that is caused by eating mad-cow-infected beef.
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- They may also be associated with Alzheimer's disease,
another degenerative and incurable brain disease, and perhaps Parkinson's
and Huntington's diseases.
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- UCSF neurologist Dr. Stanley Prusiner won the 1997 Nobel
Prize in physiology and medicine for his discovery of prions.
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- Scientists have speculated that the deformed protein
somehow acts as a template to re-shape other, healthy proteins, but have
been unable to prove this. Studies aimed at showing how TSEs are passed
from animal to animal have used tissue taken from infected animals, tissue
that could include compounds or agents other than the prions.
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- ``Although the evidence that prions cause proteins to
change shape and become infectious is quite strong, there always remained
the possibility that other molecules introduced at the same time -- sugars,
other proteins, lipids -- contributed to the infection,'' Jonathan Weissman,
an associate professor of cellular and molecular pharmacology who led the
latest study, said in a statement.
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- His team isolated pure, infectious prions and introduced
them into yeast cells. Using fluorescent proteins, they were able to show
that the yeast's own proteins were clumping together like rogue prions.
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- When the yeast divided, each new cell contained the misshapen
prion-like proteins, they reported in the journal Science.
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- The San Francisco team's yeast could not infect other
species of yeast. But research has shown that TSEs do cross the species
border.
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- Cattle are thought to have become infected with mad cow
disease after being fed the remains of scrapie-infected sheep, and scientists
agree that the new variant of CJD that has appeared in Britain came from
infected beef.
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- British officials say 76 people have become infected
with the new CJD and fear it could be the leading edge of an epidemic.
CJD, which normally infects one in a million people, takes decades to develop.
There is no cure and it always kills.
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- _____
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- Prion Shape Alone Shown To Cause Mad Cow Disease
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- Source: University Of California, San Francisco (http://www.ucsf.edu/)
Date: Posted 7/28/2000
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- UCSF Scientists Report First Direct Demonstration That
Deformed Prion Protein Shape Alone Causes Infection And Disease
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- Scientists have shown for the first time that pure prion
proteins can trigger normal proteins to change shape and become infectious.
The case for this novel form of infection has been established over the
past 20 years, but researchers have been unable to directly demonstrate
infection by pure prion proteins. The finding by scientists at the University
of California, San Francisco uses a new system to introduce prions into
yeast and eliminates the possibility that non-prion proteins, sugars and
other molecules contribute to the infection process.
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- The demonstration of pure prion infectious activity is
reported in the July 28 issue of the journal Science.
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- Prions are able to replicate, aggregate and cause deadly
infections in humans and cattle without employing genes and DNA, the first
infectious agents known to do so. They are also linked to neurodegenerative
diseases including Alzheimer's. Stanley B. Prusiner, MD, UCSF professor
of neurology and biochemistry and biophysics, won the 1997 Nobel Prize
in Physiology and Medicine for discovery of this entirely new category
of disease-causing agent and the elucidation of its mode of action.
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- Prions' ability to make copies of themselves by inducing
other proteins to take on the deformed prion shape is not only a novel
form of infection, but at least in yeast constitutes a new mode of inheritance,
says Jonathan Weissman, PhD, UCSF associate professor of cellular and molecular
pharmacology and senior author on the Science paper.
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- Over the last few years, Weissman and his colleagues
have taken advantage of a powerful genetic system in yeast for rapidly
testing the ability of a protein to change shape into a prion and to propagate
this form. The system can also test for related protein changes involved
in Alzheimer's, Parkinson's and other human diseases caused by malformed
aggregating proteins. In studies with rodents and other mammals scientists
have repeatedly shown that when prions are introduced into animals or cell
cultures, infection follows. But no one had introduced pure prions in these
experiments. Instead, the prions were derived from previously infected
animals and carried with them other molecules that could not be completely
ruled out as causing the infection, Weissman says.
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- "Although the evidence that prions cause proteins
to change shape and become infectious is quite strong, there always remained
the possibility that other molecules introduced at the same time - sugars,
other proteins, lipids -- contributed to the infection," he explains.
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- But working with yeast, the researchers faced the opposite
problem: They could readily create pure infectious prions, but there was
no clear way to introduce them into the thick-walled yeast.
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- They adapted a delivery system that had been developed
for studies of mammalian cells by Francis Szoka, Jr., PhD, UCSF professor
of biopharmaceutical chemistry.
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- The new approach largely mimics the strategy viruses
employ to introduce their DNA into hosts. Where viruses employ a two-layered
conformation known as the lipid bilayer to encapsulate infectious DNA on
its journey to its target, the UCSF researchers used synthetic spheres
called liposomes to encase the prions for delivery into the yeast. And
while viruses use co-proteins and receptors to direct their protein packets
into the right host cells, the liposome strategy uses a small molecule
called biotin to bind the liposomes and their prion cargo to the yeast.
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- Finally, in place of the viral use of so-called fusion
proteins to pierce the host's cell membrane, the UCSF strategy employed
an alcohol molecule to breach the defensive yeast cell wall.
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- "One molecule gets you in, and another breaks it
down," Weissman characterizes his team's approach.
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- With the artificial delivery system in place, the researchers
were able to show that pure prions could propagate indefinitely once they
infected the yeast cells. The team used fluorescent proteins to track changes
in shape of the infected yeast proteins, showing that the pure prions did
in fact induce the yeast protein to aggregate and adopt the prion shape.
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- The research also demonstrated that prions from one yeast
species could not infect other species. At least in yeast, the species
barrier prevents cross-species infection. The barrier has been thought
to prevent transmission of scrapie and mad cow disease from livestock to
humans, but some recent studies have found alarming evidence that in some
cases prions from cattle may infect other species, including humans.
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-
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- First author on the paper is Helmut E. Sparrer, PhD,
post-doctoral researcher in Weissman's lab. Lipsome strategist Frank Szoka
is also a co-author, as is Alex Santoso, PhD, postdoctoral fellow in the
Weissman lab. The research was supported by grants from the National Institutes
of Health, the Searle Scholars program, the David and Lucile Packard Foundation,
and the European Molecular Biology Organization.
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- Editor's Note: The original news release can be found
at http://www.ucsf.edu/pressrel/2000/07/072701.html
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- Note: This story has been adapted from a news release
issued by University Of California, San Francisco for journalists and
other members of the public. If you wish to quote from any part of this
story, please credit University Of California, San Francisco as the original
source. You may also wish to include the following link in any citation:
http://www.sciencedaily.com/releases/2000/07/000728081416.htm
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