 |
|
Brittle prions are more infectious
June 29, 2006Brittleness is often seen as a sign of fragility. But in the case of infectious proteins called prions, brittleness makes for a tougher, more menacing pathogen. Howard Hughes Medical Institute researcher have discovered that brittle prion particles break more readily into new "seeds," which spread infection much more quickly.
The discovery boosts basic understanding of prion infections, and could provide scientists with new ideas for designing drugs that discourage or prevent prion seeding, said the study's senior author Jonathan Weissman, a Howard Hughes Medical Institute investigator at the University of California, San Francisco (UCSF).
Weissman and colleagues from UCSF reported their findings on June 28, 2006, in an advance online publication in Nature.
The scientists studied yeast prions, which are similar to mammalian prions in that they act as infectious proteins. In recent years, mammalian prions have gained increasing notoriety for their roles in such fatal brain-destroying human diseases as Creutzfeldt-Jakob disease and kuru, and in the animal diseases, bovine spongiform encephalopathy ("mad cow" disease) and scrapie.
Yeast and mammalian prions are proteins that transmit their unique characteristics via interactions in which an abnormally shaped prion protein influences a normal protein to assume an abnormal shape. In mammalian prion infections, these abnormal shapes trigger protein clumping that can kill brain cells. In yeast cells, the insoluble prion protein is not deadly; it merely alters a cell's metabolism. Prions propagate themselves by division of the insoluble clumps to create "seeds" that can continue to grow by causing aggregation of more proteins.
In earlier studies, Weissman and his colleagues had discovered that the same prion can exist in different strains and have different infectious properties. These strains arise from different misfoldings of the prion protein that result in different conformations. A similar strain phenomenon has been described for mammalian prions. More generally, even in noninfectious diseases involving protein misfolding, like Alzheimer's and Parkinson's diseases, the same protein can misfold into more than one shape with some forms being toxic and others benign. However, Weissman said, it was not understood how different conformations cause different physiological effects.
As part of the studies published in Nature, the researchers created a mathematical model that enabled them to describe the growth and replication of prions according to the physical properties of the prion protein. To validate that model in yeast, they then created in a test tube, infectious forms of the prion protein in three different conformations and introduced them into yeast cells. They then correlated the strength of infectivity of each prion with its physical properties and compared their results to those predicted by their mathematical model.
According to Weissman, the researchers found that the slowest-growing conformation seemed to have the strongest effect in producing protein aggregates inside cells. "But we knew from our model that growth was only half of the equation," said Weissman. "The other key feature was how easy it was to break up the prion and create new seeds, and this propensity to seed could be an important determinant of the prion's physiological impact. And that is what we found experimentally — that the slower growth of that conformation was more than compensated for by an increased brittleness that promotes fragmentation."
According to Weissman, the importance of a prion's brittleness, or "frangibility," to its physiological effects has both basic research and clinical implications. "Investigators trying to develop synthetic prions as a research model for mammalian prions have had a very hard time getting a high degree of activity," he said. "Part of the reason may be that they were trying to create forms that were very stable. But that might have been exactly the wrong thing to do, because prions that are too stable may be the ones that are not very infectious because the aggregates are hard to break up.
"And from a therapeutic point of view, our findings suggest that effective treatment strategies for prion diseases might aim at stabilizing prion aggregates. By preventing the aggregates from being broken up to smaller seeds, their propagation can be reduced. In contrast, most such strategies now aim at preventing the proteins from forming in the first place,\\\
Howard Hughes Medical Institute
The scientists studied yeast prions, which are similar to mammalian prions in that they act as infectious proteins. In recent years, mammalian prions have gained increasing notoriety for their roles in such fatal brain-destroying human diseases as Creutzfeldt-Jakob disease and kuru, and in the animal diseases, bovine spongiform encephalopathy ("mad cow" disease) and scrapie.
Yeast and mammalian prions are proteins that transmit their unique characteristics via interactions in which an abnormally shaped prion protein influences a normal protein to assume an abnormal shape. In mammalian prion infections, these abnormal shapes trigger protein clumping that can kill brain cells. In yeast cells, the insoluble prion protein is not deadly; it merely alters a cell's metabolism. Prions propagate themselves by division of the insoluble clumps to create "seeds" that can continue to grow by causing aggregation of more proteins.
In earlier studies, Weissman and his colleagues had discovered that the same prion can exist in different strains and have different infectious properties. These strains arise from different misfoldings of the prion protein that result in different conformations. A similar strain phenomenon has been described for mammalian prions. More generally, even in noninfectious diseases involving protein misfolding, like Alzheimer's and Parkinson's diseases, the same protein can misfold into more than one shape with some forms being toxic and others benign. However, Weissman said, it was not understood how different conformations cause different physiological effects.
As part of the studies published in Nature, the researchers created a mathematical model that enabled them to describe the growth and replication of prions according to the physical properties of the prion protein. To validate that model in yeast, they then created in a test tube, infectious forms of the prion protein in three different conformations and introduced them into yeast cells. They then correlated the strength of infectivity of each prion with its physical properties and compared their results to those predicted by their mathematical model.
According to Weissman, the researchers found that the slowest-growing conformation seemed to have the strongest effect in producing protein aggregates inside cells. "But we knew from our model that growth was only half of the equation," said Weissman. "The other key feature was how easy it was to break up the prion and create new seeds, and this propensity to seed could be an important determinant of the prion's physiological impact. And that is what we found experimentally — that the slower growth of that conformation was more than compensated for by an increased brittleness that promotes fragmentation."
According to Weissman, the importance of a prion's brittleness, or "frangibility," to its physiological effects has both basic research and clinical implications. "Investigators trying to develop synthetic prions as a research model for mammalian prions have had a very hard time getting a high degree of activity," he said. "Part of the reason may be that they were trying to create forms that were very stable. But that might have been exactly the wrong thing to do, because prions that are too stable may be the ones that are not very infectious because the aggregates are hard to break up.
"And from a therapeutic point of view, our findings suggest that effective treatment strategies for prion diseases might aim at stabilizing prion aggregates. By preventing the aggregates from being broken up to smaller seeds, their propagation can be reduced. In contrast, most such strategies now aim at preventing the proteins from forming in the first place,\\\
Howard Hughes Medical Institute
Prions News and Current Prions Events RSSStudy confirms vCJD could be transmitted by blood transfusion
The findings underline the importance of precautions against vCJD transmission, such as the Government decision in 2004 to ban blood donations from anyone who had received a blood transfusion since 1980.
Deadly dose: Rensselaer heparin expert helps uncover source of lethal contamination
The mysterious death of patients around the world following a routine dosage of the common blood thinner, heparin, sent researchers on a frantic search to uncover what could make the standard drug so toxic.
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.
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.
Scientists identify prion's infectious secret
Researchers 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.
Vaccine prevents prion disease in mice
An oral vaccine can prevent mice from developing a brain disease similar to mad cow disease.
Scripps research study reveals structural dynamics of single prion molecules
New techniques paint clearer picture of amyloid formation associated with protein-based inheritance and neurodegenerative diseases such as mad cow, Alzheimer's.
The CReSA is working on a new strategy to combat spongiforms
Researchers at the Animal Health Research Centre (CReSA) are developing immunotherapeutical strategies against diseases produced by prion, such as Bovine Spongiform Encephalitis.
Prion disease agent causes heart damage in mouse study
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.
More Prions News Articles
 | The Family That Couldn't Sleep: A Medical Mystery by D.T. Max For two hundred years a noble Venetian family has suffered from an inherited disease that strikes their members in middle age, stealing their sleep, eating holes in their brains, and ending their lives in a matter of months. In Papua New Guinea, a primitive tribe is nearly obliterated by a sickness whose chief symptom is uncontrollable laughter. Across Europe, millions of sheep rub their fleeces... |
 | Things a Woman Should Know About Style (Things A Woman Should Know Series) by Karen Homer Firm but always fair, Karen Homer lays down the law to ensure that you never commit another fashion faux pas. Discover why you can never have too many white T-shirts, how to choose the right shoes and lingerie, and when to say “no” to this season’s fashion trends. Packed with tips and timeless rules, enhanced with classic photos of style icons, this chic little volume will never... |
 | A Well-Dressed Gentleman's Pocket Guide by Oscar Lenius While fashion is subject to seasonal change, the wardrobe of the man who dresses in classic style is marked by a distinctive continuity. A Well-Dressed Gentleman’s Pocket Guide is both an etiquette and a history of impeccable dressing and classic styling. It illustrates the fine distinctions of the gentleman’s dress code, arming the reader with the requisite information to dress for... |
 | Deadly Feasts: The "Prion" Controversy and the Public's Health by Richard Rhodes The British epidemic of bovine spongiform encephalopathy, or "mad cow" disease, is only one in a series of mysterious and often fatal afflictions that have baffled scientists for more than 40 years. Deadly Feasts is a compelling account of decades of research into a family of diseases ranging from kuru in primitive human tribes to scrapie in sheep. Richard Rhodes traces the attempts of scientists... |
 | Amazonia: A Novel by James Rollins From James Rollins, national bestselling author of Subterranean, Excavation, and Deep Fathom, comes a breathtaking masterwork of extraordinary adventure -- a gripping journey into a wilderness of astonishing mysteries as deadly as they are unfathomable.AMAZONIAOut of the world's most inhospitable rainforest, a man stumbles into a small missionary village. Within hours, the CIA operative and... |
 | The Diary of a Nobody (Prion Humour Classics) by George Grossmith, Weedon Grossmith "Why should I not publish my diary? I have often seen reminiscences of people I have never even heard of, and I fail to see, because I do not happen to be a "Somebody," why my diary should not be interesting." So wrote the anxious, accident-prone, occasionally waspish, Charles Pooter, who has come to be seen as the epitome of English suburban life. His diary chronicles encounters with difficult... |
 | Sex Lives of the Kings and Queens (Sex Lives) by Nigel Cawthorne Prion’s internationally bestselling Sex Lives series presents lighthearted accounts of the sexual escapades of major figures in history, politics, religion, the arts, and film. Irreverent and gossipy, the books are packed with carnal tidbits and eye-opening revelations. The headlines of Royal infidelity and divorce that are the bread and butter of today's tabloid press are nothing new.... |
 | Sex Lives of the Popes (Sex Lives) by Nigel Cawthorne Prion’s internationally bestselling Sex Lives series presents lighthearted accounts of the sexual escapades of major figures in history, politics, religion, the arts, and film. Irreverent and gossipy, the books are packed with carnal tidbits and eye-opening revelations. In the last 2,000 years the Popes have set the sexual agenda for almost a quarter of the world's population. But while... |
 | She Tried to Be Good: Sirens and Vamps from the Pulp Classics (Pulp Postcards) by Prion Pulp Postcard Book As America slowly relaxed its moral codes in the postwar era, pulp novels offered an initiation to the previously hidden demimondes of sex and hedonistic excess. While the cover blurbs feigned shock and disgust, the cover art reveled in illicit danger, their titillating scenarios offering a lurid window on America’s suppressed desires. Now, collected here, are tigresses and temptresses in... |
 | Myths and Legends of the Martial Arts by Peter Lewis These colorful tales trace the origins and illuminate the philosophies of each of the martial arts. Karate, kung fu, judo, aikido, sumo—each discipline of the martial arts is, at its most developed point, as much a philosophy as a code of war. Like any culture, each martial art has its founding myths, which reveal its origins and make sense of its underlying principles. These vivid parables... |
| © 2008 BrightSurf.com |