Two teams of scientists have gleaned clues about the mysterious link between
an abnormally folded protein and some of the most deadly and bizarre brain
disorders, including "mad cow" disease.
Among other findings, the scientists uncovered evidence that the proteins,
called prions, can jump across species barriers and lead to brain-degenerating
infections such as the human Creutzfeldt-Jakob disease that can result
from eating contaminated meat, they reported in the British journal Nature.
In one study, investigators prodded a muscle protein to take on an abnormal
structure reminiscent of the clumping observed in the brain of patients
with Alzheimer's and CJD, indicating more proteins than had been thought
might be susceptible to the aberration.
In the second study, scientists fused yeast cells to compose a "promiscuous"
hybrid capable of jumping the species barrier and infecting proteins from
two distantly related species of yeast.
"It may be time to consider the disturbing possibility that certain bovine
prion forms have an enhanced ability to cross the species barrier to humans,"
said Susan Liebman of the University of Illinois in Chicago, who wrote
an accompanying News and Views article.
The studies have important implications for the prevention and treatment
of an array of "aggregation" diseases such bovine spongiform encephalopathy,
commonly called mad cow, in cattle, scrapie in sheep and CJD, Alzheimer's,
diabetes and Parkinson's in humans, investigators said.
In a healthy organism, each of the thousands of proteins in every cell
is folded into just the right shape to function. In prion diseases, a normal
cell protein assumes an abnormal shape. The badly folded proteins meet
their end but not before casting an infectious influence over other proteins.
As more and more proteins fold into the prion shape, they form inactive
clumps that can lead to dysfunction and disease.
Both new studies suggest it might be far easier for proteins to form these
abnormal structures than had been thought, scientists said.
"The significance of this study is that it gives a fundamental structural
explanation of the general nature and origins of the whole group of aggregation
diseases that include Alzheimer's, BSE and the other prion diseases including
CJD, late-onset diabetes and even Parkinson's," Christopher Dobson of the
University of Oxford, lead author of one study, told United Press International
from Florence, Italy.
"It will not immediately lead to new therapies, but this new understanding
could enable novel strategies to be developed to devise fundamentally new
means of treatment or prevention."
The findings in the second study support a once ridiculed notion. "We have
established the basic principal that a single pure protein can adopt to
infectious conformations," lead author Jonathan Weissman of the University
of California, San Francisco, told UPI.
"This is an idea that Charles Weissmann (a prion expert now at Imperial
College School of Medicine at St. Mary's in London) in a recent News and
Views in Nature said that more than one protein biochemist considered 'insane.'"
"Our work and the studies on strains in mad cow disease underscore the
importance of understanding these shape differences for both the diagnosis
and hopefully treatment of prion diseases," Weissman said.
In the Oxford study, Dobson and team were able to induce the muscle protein
myoglobin to assume the abnormal structure characteristic of Alzheimer's
and CJD. The aggregates are not identical; there is a different protein
sequence found in each disease, but the underlying structures are "very
similar" to each other, the scientists said.
"Our observations begin to explain the origin of similar transformations
in the series of familial (genetic) and aging diseases that are related
to the prion diseases in having deposits of aggregated proteins within
a variety of tissues," Dobson said.
The findings indicate that many proteins could be made to assume these
structures but they do not because organisms have evolved ways to hold
them at bay.
"Our thought is that many, perhaps all, proteins could form such material
but that the biological environment and its control mechanisms ... have
evolved such that these species do not form under 'normal' conditions,"
Dobson said. "Aging, mutations, and perhaps the ingestion of aggregated
prions could in principle undermine these regulatory processes by changing
the environment or the protein behavior or maybe just causing the process
to speed up."
"We are in this sense living with protein structures that are being prevented
from converting to the 'natural' aggregated states," Dobson said. "As we
get older, these proteins tend to escape from these protective mechanisms,
and we begin to turn solid!"
In their study, Weissman and colleagues used yeast, the organism found
in bread and beer. Yeast prions, discovered only a few years ago, are not
related to mammalian prions and do not harm humans or yeast. Their usefulness
in the laboratory comes from their unusual property of misfolding in the
same peculiar way as mammalian prions and spreading their change in shape
from one protein to another.
The hybrid produced by stitching together segments of two species of yeast
prions can adopt two distinct infectious shapes and, thus, bridge a species
barrier and infect prions from two distantly related species of yeast.
"We found that this chimera was 'promiscuous,'" Weissman said. "We cannot
take comfort in the fact that the cow prion protein has a different sequence
than the human prion, because if the cow prion has assumed a conformation
that's virulent in humans, it won't be held up effectively by a species
barrier," he said."
The study also indicates that the treatment of prion-containing meat might
have the opposite of the desired effect. "What we are learning from both
yeast and mammalian prions raises the disturbing possibility that the process
of infecting, heat-rendering of the animal parts, and then re-infecting
cows might actually have selected for a prion strain conformation that
is particularly virulent and resistant to being inactivated," Weissman
said. "So, it might have been this very process that humans set up that
made the bovine prion so virulent and created the epidemic of mad cow disease."
Possible solutions are complex, the scientists said. Ideas that are "out
there but not yet close to general application" include formulating compounds
that might prevent the protein abnormality, enhancing the body's own clump-clearing
mechanisms and developing vaccines to help prevent or clean out the aggregates.
"In the longer term, as we have shown, we could design improved proteins
that are more stable or less prone to aggregate," Dobson said. "Gene therapy
in this sense might help. But the latter is a long way away.
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Copyright
2001 by United Press International.
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rights reserved.
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