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Prion disease agent causes heart damage in mouse study
July 10, 2006Findings suggest that neurodegenerative disease affects other tissues
These findings raise the possibility that heart infection could be a new aspect of prion diseases, including those that affect humans and livestock, and that these diseases could travel through the blood.
The paper is being published on Friday, July 7 in an advanced, online edition of the journal Science.
Prion diseases-also known as transmissible spongiform encephalopathies because of the sponge-like holes created in the brain-include scrapie in sheep, mad cow disease in cattle, chronic wasting disease in deer and elk, and new variant Creutzfeldt-Jacob disease in humans. These diseases are unusual because unlike other infectious diseases, prion diseases appear to be transmitted by a protein, specifically a misfolded form of a normal cellular protein, the prion.
"Until now, prion disease has been thought of as a chronic neurological condition," says Scripps Research Professor Michael B. Oldstone, M.D., who led the research. "Our study has shown, however, that it can have other manifestations, therefore expanding the types of conditions it could cause."
In the newly reported study, investigators at Scripps Research found infectious misfolded prion protein in heart muscle. Although several types of protein are known to form heart amyloid, this is the first time prion protein amyloid in heart tissue has been identified. Only misfolded prion proteins are infectious.
After making this surprising finding, Scripps Research investigators secured the help of Kirk Knowlton, M.D., chief of the division of cardiology at the University of California, San Diego, who investigated the effect of prion protein amyloid on mouse heart function, discovering that it decreased the heart's ability to pump blood.
Significantly, unusually high levels of scrapie infectivity were also identified in the blood of the same mice used in the heart study. "This is the first system in which prion disease agents were found reproducibly and reliably at high titers in the blood," notes Oldstone.
In the future, this finding could help scientists answer basic questions such as how prions travel in the bloodstream, as well as develop such important applications as a blood-based diagnostic test to identify brain-wasting diseases and possibly a way to filter or chemically treat blood to remove any infectious prion disease agents. Currently, in the United States individuals who lived in the United Kingdom for three months or more during the outbreak of mad cow disease from 1980 to 1996 are asked not to donate blood. In the United Kingdom, only individuals born after the outbreak may donate.
The new research will also provide scientists with an animal model in which to study heart amyloidosis, a family of heart diseases that affect humans. Amyloidoses involve waxy protein deposits that stiffen the heart, limit its pumping ability, and typically lead to fatal heart stoppage.
"Undoubtedly, this work will enable scientists to pursue new theories about the effects of these deadly brain wasting diseases," says NIH Director Elias A. Zerhouni, M.D. "The implications of this research could be vital to our efforts to slow or stop these diseases."
The new research follows last year's finding from the Oldstone group in collaboration with Bruce Chesebro, M.D., at the NIH's Rocky Mountain Laboratories, which suggested a specific part of the prion protein is essential for the pathogenesis of prion diseases (Science (308 (5727):1435-39 (2005)). In this study, the investigators engineered scrapie-infected mice without an "anchor"-specifically the glycophosphoinositol anchor, a stretch of amino acids at the COOH end of the protein-between the membrane of cells and the prion protein. By taking off this anchor, the researchers showed that the prion protein still folded but was no longer able to attach in normal amounts onto the surface of cells. In contrast to scrapie-infected wild mice, which typically die after about 150 days, the engineered mice regularly lived for more than 600 days with minimal symptoms, ultimately dying of old age.
In prion diseases, the normal form of the prion protein is converted into an abnormal, misfolded form. Disease occurs because these abnormal proteins have the ability to convert normal prion proteins into the abnormal form. Like bad apples spoiling the lot, the infectious prions will multiply, and their insolubility will lead to their aggregation and the formation of plaques, which can interfere with normal function in the brain.
Of the prion diseases, most in the news has been bovine spongiform encephalopathy, or mad cow disease, which has caused widespread public concern over the last two decades after it has appeared primarily in cattle in England but also in other countries in Europe, Canada, and the United States. Perhaps the number one reason why a disease that infects cows is of such concern to world governments is that scientists believe that the disease can be transmitted across species through the consumption of tainted meat from a diseased animal's central nervous system. The first major outbreak of mad cow disease in Britain is believed to have originated with the now outlawed practice of feeding cattle meat and bone meal derived from other slaughtered animals. Chronic wasting disease in U.S. deer and elk is also of concern, as the abnormal protein has been found in both wild and farmed animals.
Scientists now know that humans who eat meat from BSE-infected cattle may be susceptible to the prion disease new variant Creutzfeldt-Jakob. There are now more than 140 such cases. This incurable disease is named after a similar condition called Creutzfeldt-Jakob disease, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob, who first diagnosed it. Creutzfeldt-Jakob disease most commonly strikes older people, and it causes neurologic abnormalities, dementia, memory loss, hallucinations, seizures, and eventually death. New variant Creutzfeldt-Jakob is similar clinically, but can strike much younger people. According to the U.S. Centers for Disease Control and Prevention, the median age of death for Americans with Creutzfeldt-Jakob disease is 68, whereas the median age of death of people with new variant Creutzfeldt-Jakob in Great Britain, where most cases have occurred, is 28.
Scripps Research Institute
Prion diseases-also known as transmissible spongiform encephalopathies because of the sponge-like holes created in the brain-include scrapie in sheep, mad cow disease in cattle, chronic wasting disease in deer and elk, and new variant Creutzfeldt-Jacob disease in humans. These diseases are unusual because unlike other infectious diseases, prion diseases appear to be transmitted by a protein, specifically a misfolded form of a normal cellular protein, the prion.
"Until now, prion disease has been thought of as a chronic neurological condition," says Scripps Research Professor Michael B. Oldstone, M.D., who led the research. "Our study has shown, however, that it can have other manifestations, therefore expanding the types of conditions it could cause."
In the newly reported study, investigators at Scripps Research found infectious misfolded prion protein in heart muscle. Although several types of protein are known to form heart amyloid, this is the first time prion protein amyloid in heart tissue has been identified. Only misfolded prion proteins are infectious.
After making this surprising finding, Scripps Research investigators secured the help of Kirk Knowlton, M.D., chief of the division of cardiology at the University of California, San Diego, who investigated the effect of prion protein amyloid on mouse heart function, discovering that it decreased the heart's ability to pump blood.
Significantly, unusually high levels of scrapie infectivity were also identified in the blood of the same mice used in the heart study. "This is the first system in which prion disease agents were found reproducibly and reliably at high titers in the blood," notes Oldstone.
In the future, this finding could help scientists answer basic questions such as how prions travel in the bloodstream, as well as develop such important applications as a blood-based diagnostic test to identify brain-wasting diseases and possibly a way to filter or chemically treat blood to remove any infectious prion disease agents. Currently, in the United States individuals who lived in the United Kingdom for three months or more during the outbreak of mad cow disease from 1980 to 1996 are asked not to donate blood. In the United Kingdom, only individuals born after the outbreak may donate.
The new research will also provide scientists with an animal model in which to study heart amyloidosis, a family of heart diseases that affect humans. Amyloidoses involve waxy protein deposits that stiffen the heart, limit its pumping ability, and typically lead to fatal heart stoppage.
"Undoubtedly, this work will enable scientists to pursue new theories about the effects of these deadly brain wasting diseases," says NIH Director Elias A. Zerhouni, M.D. "The implications of this research could be vital to our efforts to slow or stop these diseases."
The new research follows last year's finding from the Oldstone group in collaboration with Bruce Chesebro, M.D., at the NIH's Rocky Mountain Laboratories, which suggested a specific part of the prion protein is essential for the pathogenesis of prion diseases (Science (308 (5727):1435-39 (2005)). In this study, the investigators engineered scrapie-infected mice without an "anchor"-specifically the glycophosphoinositol anchor, a stretch of amino acids at the COOH end of the protein-between the membrane of cells and the prion protein. By taking off this anchor, the researchers showed that the prion protein still folded but was no longer able to attach in normal amounts onto the surface of cells. In contrast to scrapie-infected wild mice, which typically die after about 150 days, the engineered mice regularly lived for more than 600 days with minimal symptoms, ultimately dying of old age.
In prion diseases, the normal form of the prion protein is converted into an abnormal, misfolded form. Disease occurs because these abnormal proteins have the ability to convert normal prion proteins into the abnormal form. Like bad apples spoiling the lot, the infectious prions will multiply, and their insolubility will lead to their aggregation and the formation of plaques, which can interfere with normal function in the brain.
Of the prion diseases, most in the news has been bovine spongiform encephalopathy, or mad cow disease, which has caused widespread public concern over the last two decades after it has appeared primarily in cattle in England but also in other countries in Europe, Canada, and the United States. Perhaps the number one reason why a disease that infects cows is of such concern to world governments is that scientists believe that the disease can be transmitted across species through the consumption of tainted meat from a diseased animal's central nervous system. The first major outbreak of mad cow disease in Britain is believed to have originated with the now outlawed practice of feeding cattle meat and bone meal derived from other slaughtered animals. Chronic wasting disease in U.S. deer and elk is also of concern, as the abnormal protein has been found in both wild and farmed animals.
Scientists now know that humans who eat meat from BSE-infected cattle may be susceptible to the prion disease new variant Creutzfeldt-Jakob. There are now more than 140 such cases. This incurable disease is named after a similar condition called Creutzfeldt-Jakob disease, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob, who first diagnosed it. Creutzfeldt-Jakob disease most commonly strikes older people, and it causes neurologic abnormalities, dementia, memory loss, hallucinations, seizures, and eventually death. New variant Creutzfeldt-Jakob is similar clinically, but can strike much younger people. According to the U.S. Centers for Disease Control and Prevention, the median age of death for Americans with Creutzfeldt-Jakob disease is 68, whereas the median age of death of people with new variant Creutzfeldt-Jakob in Great Britain, where most cases have occurred, is 28.
Scripps Research Institute
Prion Current Events and Prion News RSSThe Protein Srebp2 Drives Cholesterol Formation in Prion-Infected Neuronal Cells Which May Promote Prion-Dependent Diseases
The regulating protein Srebp2 drives cholesterol formation, which prions need for their propagation, in prion-infected neuronal cells.
Prion study reveals first direct information about the protein's molecular structure
A collaboration between scientists at Vanderbilt University and the University of California, San Francisco has led to the first direct information about the molecular structure of prions.
U of T led research team uncovers evolutionary origins of prion disease gene
A University of Toronto-led team has uncovered the evolutionary ancestry of the prion gene, which may reveal new understandings of how the prion protein causes diseases such as bovine spongiform encephalopathy (BSE), also known as "mad cow disease."
Species barrier may protect macaques from chronic wasting disease
Data from an ongoing multi-year study suggest that people who consume deer and elk with chronic wasting disease (CWD) may be protected from infection by an inability of the CWD infectious agent to spread to people.
A Penny for Your Prions
North Carolina State University researchers have discovered a link between copper and the normal functioning of prion proteins, which are associated with transmissible spongiform encephalopathy diseases such as Cruetzfeldt-Jakob in humans or "mad cow" disease in cattle.
Scripps Florida scientists devise accelerated method to determine infectious prion strainsScripps Florida scientists devise accelerated method to determine infectious prion strains
Current tests to identify specific strains of infectious prions, which cause a range of transmissible diseases (such as mad cow) in animals and humans, can take anywhere from six months to a year to yield results - a time-lag that may put human populations at risk.
Prevalence of variant CJD agent in Britain remains uncertain
First results from a large tissue survey in Britain of the agent that causes variant Creutzfeldt-Jakob disease (vCJD) are unable so far to establish that the prevalence is lower than that given by previous estimates, concludes a study published on bmj.com today.
Redefining what it means to be a prion
Whitehead Institute researchers have quintupled the number of identifiable prion proteins in yeast and have further clarified the role prions play in the inheritance of both beneficial and detrimental traits.
Iron is involved in prion disease-associated neuronal demise
Imbalance of iron homeostasis is a common feature of prion disease-affected human, mouse, and hamster brains, according to a new study by Dr. Neena Singh and colleagues at Case Western Reserve University School of Medicine, alongside collaborators from Creighton University.
Prion discovery gives clue to control of mass gene expression
The discovery in common brewer's yeast of a new, infectious, misfolded protein -- or prion -- by University of Illinois at Chicago molecular biologists raises new questions about the roles played by these curious molecules, often associated with degenerative brain diseases like "mad cow" and its human counterpart, Creutzfeldt-Jakob.
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The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases by Philip Yam (Author) In 1996, British doctors were horrified to discover that mad cow disease (BSE), an affliction that had been plaguing British cattle for ten years, had jumped the species barrier and was appearing in humans as variant Creutzfeldt-Jakob disease (vCJD). Not unlike the mad cows, victims of vCJD suffer from a degenerative neurological disease that peppers the brain with microscopic holes, causing dementia, loss of motor control, and certain death. What alarms researchers and public health officials worldwide is that the incubation period for vCJD may be as long as 10 or even 15 years, and during this period those infected are symptom-free. And because the disease is so far undetectable except by autopsy, there is no way of knowing with certainty how many people have already been infected. In... |
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Prions: The New Biology of Proteins by Claudio Soto (Author) The current interest in prion diseases has been fueled by the panic that originated from the appearance of a new variant of Creutzfeldt-Jakob disease and the evidence linking it to human exposure to the bovine spongiform encephalopathy (BSE) agent. Peer-reviewed to assure accuracy, this book describes the science, concepts, hypothesis, and mechanisms of prion disease transmission. It covers human and animal prion diseases, their incidence, prevalence, origin, and clinical and neuropathologic characteristics. The author provides scientific facts and a clear explanation of the relevance and implications of the findings for science in general. |
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Deadly Feasts: The "Prion" Controversy and the Public's Health by Richard Rhodes (Author) In this brilliant and gripping medical detective story. Richard Rhodes follows virus hunters on three continents as they track the emergence of a deadly new brain disease that first kills cannibals in New Guinea, then cattle and young people in Britain and France -- and that has already been traced to food animals in the United States. In a new Afterword for the paperback, Rhodes reports the latest U.S. and worldwide developments of a burgeoning global threat. |
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