Scientists identify prion's infectious secretMay 10, 2007Researchers have known for decades that certain neurodegenerative diseases, such as mad cow disease or its human equivalent, Cruetzfeldt-Jakob disease, result from a kind of infectious protein called a prion. Remarkably, in recent years researchers also have discovered non-pathogenic prions that play beneficial roles in biology, and prions even may act as essential elements in learning and memory. But although prions have received a great deal of scrutiny, scientists still don't understand many of the most fundamental mechanisms of how prions form, replicate and cross from one species to another. Now, through studying non-toxic yeast prions, scientists at Whitehead Institute have discovered small but critical regions within prions that determine much of their behavior.
"These findings provide a new framework for us to begin exploring properties of prion biology that, up until now, have proven difficult to investigate," says Whitehead Member and MIT Professor of Biology Susan Lindquist, senior author on the paper, which will appear in the May 9 online issue of Nature. Proteins are the cell's workhorses, and they need to fold into complex and precise shapes to do their jobs. Prions are proteins that start out normally, but then at some point misfold—rather like an origami swan that comes out looking and acting instead like a vulture. But prions have another characteristic that enables them to wreak havoc. They recruit other, properly folded proteins into misforming along with them, a process Lindquist calls a "conformational cascade." In many organisms, this conformational cascade creates long fibers called amyloids. (The brains of animals that have died from prion infections are literally packed with amyloid clumps.) In order to glean insights into the mechanics that enable amyloid formation, Peter Tessier, a postdoctoral scientist in Lindquist's lab, used peptide arrays—glass slides covered with thousands of tiny protein fragments. Traditionally, these arrays are used for finding binding sites within well-behaved proteins. Here, Tessier designed the arrays so that he could observe protein folding and amyloid formation in real time. Tessier covered the array with peptides from baker's yeast and then added prion protein to the array, also from the same yeast species. He found that a small cluster of peptides recruited the prion proteins to misfold into an amyloid structure. This region of the protein, which Tessier called a "recognition element," constitutes about 10 percent of the prion. Tessier repeated this experiment with peptides and a prion taken from pathogenic fungi. The results were the same. Both prions also maintained a rigid species barrier. The baker's yeast prion could not recruit peptides from the pathogenic fungi cells, and vice versa. To further verify these results, Tessier accessed a synthetic yeast prion, one that another research group had assembled from pieces of both the baker's yeast and the pathogenic fungi prion. Earlier studies had shown that this synthetic prion could cross the species barrier but did not identify the mechanism. Tessier found that this synthetic prion contained two recognition elements, one for baker's yeast and one for pathogenic fungi. When the prion was placed with peptide fragments from baker's yeast, the baker's yeast recognition element was activated, and likewise for the pathogenic fungi. Even more striking, Tessier could activate different recognition elements by manipulating environmental conditions, such as temperature. For example, when he conducted the experiment at 4 degrees Celsius, the baker's yeast recognition element switched on. At 37 degrees Celsius, the pathogenic fungi element was activated. In other words, temperature alone could dictate which yeast species the prion could infect. Additionally, the prion's behavior could be altered by subtle alterations in the recognition element's amino acid sequence. While this prion is a laboratory construct not found in nature, these findings provide researchers with a new way to approach old questions, such as why some prion diseases can jump from one species to another but others can't. Tessier and Lindquist say it is likely that natural prions contain more than one recognition element, and recognition elements can slide into a neighboring region. Many external factors can determine which recognition element is activated, in turn influencing the downstream behavior of the prion. "These findings are remarkable for two reasons," says Lindquist, who is also an investigator for Howard Hughes Medical Institute. "For one thing, this is the first time that these peptide arrays have been used to study protein folding. We've taken this platform to a whole new level. Also, we've seen just one small part of this prion inducing proteins to fold. This is an entirely new concept." Earlier research from the Lindquist lab, published in Nature in 2005, identified the amino acid regions where prions connect with one another to form amyloids. Those interaction regions turn out to be the same regions Tessier identified as recognition elements— further confirmation that these regions are key to prion activity. Tessier and his colleagues plan to further investigate this process in mammalian prions, such as those responsible for mad cow and Cruetzfeldt-Jakob diseases, as well as in other non-prion proteins that can also form amyloid structures. Whitehead Institute for Biomedical Research | |||||||||||||||||||||
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Related Prion News Articles 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. New prion protein discovered by Canadian scientists may offer insight into mad cow disease Scientists have discovered a new protein that may offer fresh insights into brain function in mad cow disease. "Our team has defined a second prion protein called 'Shadoo', that exists in addition to the well-known prion protein called 'PrP' " said Professor David Westaway, director of the Centre for Prions and Protein Folding Diseases at the University of Alberta. Newly discovered antibody may be body's natural defense against Alzheimer's In an important advance in the battle against Alzheimer's disease, physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center have identified naturally occurring antibodies in human blood that may help to defend against this form of dementia as well as other neurodegenerative diseases. NMR advance relies on microscopic detector Detecting the molecular structure of a tiny protein using nuclear magnetic resonance (NMR) currently requires two things: a million-dollar machine the size of a massive SUV, and a large sample of the protein under study. More Prion News Articles |
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