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 published in 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.