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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 RSSIs there more to prion protein than mad cow disease?
Prion protein, a form of protein that triggers BSE, is associated with other brain diseases in cattle, raising the possibility of a significant increase in the range of prion disease.
K-State professor's USDA research shows mad cow disease also caused by genetic mutation
New findings about the causes of mad cow disease show that sometimes it may be genetic.
Changes in urine could lead to BSE test for live animals
Researchers have demonstrated that protein levels in urine samples can indicate both the presence and progress of Bovine Spongiform Encephalopathy (BSE) disease in cattle.
How small molecule can take apart Alzheimer's disease protein fibers
Researchers from the University of Pennsylvania School of Medicine have shown, in unprecedented detail, how a small molecule is able to selectively take apart abnormally folded protein fibers connected to Alzheimer's disease and prion diseases.
Europe develops new technologies to boost health of livestock
A range of new technologies including genetic modification (GM) and RNA Interference are being deployed to improve the health of farm animals in a series of European and global initiatives. The ground was laid for a European platform to develop new treatments that exploit these technologies at a recent workshop organised by the European Science Foundation (ESF).
New insights into the diversity of Creutzfeldt-Jakob disease agents
Researchers from the United Kingdom and France have identified four separate biochemical subgroups in a selection of cases of Creutzfeldt-Jakob disease.
Prions link cholesterol to neurodegeneration
Prion infection of neurons increases the free cholesterol content in cell membranes. A new study published in the online open access journal BMC Biology suggests that disturbances in membrane cholesterol may be the mechanism by which prions cause neurodegeneration and could point to a role for cholesterol in other neurodegenerative diseases.
Scripps scientists develop new tests that identify lethal prion strains quickly and accurately
One of the new in vitro tests, called the Standard Scrapie Cell Assay, measures prion infectivity levels in a highly accurate and extremely rapid way, producing results in less than two weeks.
UIC chemists characterize Alzheimer's neurotoxin structure
Amyloid plaques, the hallmark of Alzheimer's disease, are clumps of fiber-like misfolded proteins which many experts think cause this devastating neurodegenerative disease.
First high-res 3D structures of mammalian HSP90 protein solved
Dr. Dan Gewirth, Hauptman-Woodward senior research scientist, has just solved the structure of the first mammalian GRP94 protein implicated in immune diseases such as sepsis, AIDS and certain cancers.
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