Biological Psychology Links

By Caroline Parkinson A new form of brain disease, similar to Creutzfeld-Jakob Disease, could affect more people than previously thought, researchers in the US say. It had been thought that only people with one genetic profile were vulnerable to the prion disease VPSPr. But in an Annals of Neurology study, Case Western Reserve University experts found people with all three possible gene patterns are affected by VPSPr. They say the findings could help with the treatment of prion diseases. Although it is a prion disease like vCJD, VPSPr is not linked to eating infected meat. However, like CJD, the new condition happens sporadically. It was first identified because of the fast-advancing form of dementia seen in those affected. They were also unable to speak or move. But tests for CJD proved negative. Further molecular examination showed VPSPr was a prion disease, but one which looked very different to those already known. The human prion protein gene comes in three variants, depending on which amino acid the prion proteins contain - valine (V) or methionine (M). People can be VV, MM or MV. The first clutch of cases identified all had the VV variant. However, these latest cases included people with the other variants too. Despite extensive research, a relatively large group of neurodegenerative diseases associated with dementia remain undefined. (C)BBC

Daniel Cressey After an epic series of experiments, a group of researchers has observed and reproduced what could be the spontaneous generation of prions ā€” rogue misfolded proteins that have been implicated in the destruction of the central nervous system. These misfolded proteins, the culprits in Creutzfeldtā€“Jakob disease and scrapie, are highly infectious. Although famously transmitted by the ingestion of infected meats, prions are also thought to arise spontaneously in a tiny fraction of humans and other animals. Such de novo prion generation has previously been achieved with animal cells using a method called 'protein misfolding cyclic amplification' (PMCA), which involves repeated rounds of ultrasound and incubation. Now, a London-based team reports observing prions appearing from healthy mouse brain tissue1. (Human samples have traditionally proved less amenable to PMCA, and the misfolding of prion proteins is believed to occur at a much lower rate in humans than in mice.) "What we were doing was trying to develop a very sensitive assay for prion detection on a metal surface, so we could use that in prion decontamination," says co-author John Collinge, who heads up the Department of Neurodegenerative Disease at University College London. "It took a while before we could convince ourselves this was a real phenomenon." Ā© 2010 Nature Publishing Group

The US has found its second case of mad cow disease in a cow suspected, but cleared, of having BSE in November 2004. Although meat from the cow did not enter the food chain, the finding calls into question the accuracy of the country’s BSE surveillance programme. The cow might also be the first case born in the US. The first US case was in a cow imported from Canada in 2003. In 2004 the country started testing “high-risk” cattle - those that show neurological symptoms, are found dead or are “downers” (unable to stand). Since then it has tested 375,000 cattle. None were declared positive. In contrast, Canada has tested 30,000 cattle and found three positives. The rate at which the tests uncover positive cattle depends on the sample size, stresses Marcus Doherr of the University of Bern in Switzerland, who helped develop Swiss BSE surveillance. This means either that BSE is less evenly distributed in North America than thought, or that the US is missing cases. Unlike Canada, which uses the rapid “western blot” test, the US uses a test called ELISA, which is more prone to false positives. In 2004 the ELISA test detected three BSE positive cattle in the US. When these brains were re-tested, the ELISA was negative. Then they were subjected to immunohistochemistry (IHC) testing - a thin slice of brain is stained with antibodies for the prion protein that causes BSE. All were negative, and the cattle were declared BSE-free. “But if the prion is diffuse enough in the brain tissue, you can get a weak signal with the ELISA, and a negative with IHC,” says Doherr. Another test is needed to be certain, he says. © Copyright Reed Business Information Ltd

Roxanne Khamsi Proteins taken from the brains of Alzheimer’s patients and injected into the brains of genetically engineered mice trigger Alzheimer’s-like lesions in the mouse brains, researchers report. The findings suggest that the malformed protein clumps associated with Alzheimer’s disease can “seed” themselves in a way reminiscent of the missfolded proteins in prion diseases such as “mad cow” disease. The exact causes of Alzheimer’s remain a mystery, but it appears that beta-amyloid proteins contribute to the formation of disruptive plaques in the brain. The neurological damage accumulates over years, causing loss of memory, language and other crucial mental skills. Experts studying how beta amyloid might promote plaque formation have speculated that this might happen in a process similar to that in prion diseases. Prion illnesses, such as mad cow disease, are special in that proteins apparently act as the infectious agents, rather than genetic material or a microorganism. In laboratory tests, animals that receive prion proteins develop brain plaques and eventually die as a result. © Copyright Reed Business Information Ltd.

By Laura Sanders Prion protein, notorious for causing the brain-wasting mad cow and Creutzfeldt-Jakob diseases, may also be a coconspirator in Alzheimer’s disease, a new study in mice suggests. In mad cow and Creutzfeldt-Jakob diseases, misshapen prion proteins do the damage. But the new paper, appearing February 26 in Nature, offers evidence that the harmless version of the prion protein assists the amyloid-beta protein responsible for brain cell death in Alzheimer’s disease. “It’s pretty sensational,” comments Adriano Aguzzi, a neuropathologist at the University of Zurich. “What’s tremendously electrifying is that prion protein may be a genetic sensor for extremely toxic, small concentrations of A-beta.” A-beta proteins can travel alone or in groups in the brain. On their own, A-beta proteins are harmless. Massive, insoluble clumps of A-beta, known as plaques, are probably harmless, too, says study coauthor Stephen Strittmatter, a neuroscientist at Yale University. These plaques may be a gravestone marker of dead brain cells but are probably not the killer. Instead, smaller, soluble clumps of 50 to 100 A-beta proteins, known as oligomers, are the most likely suspect, Strittmatter says. Earlier studies have shown that mice with A-beta oligomers can’t remember how to get through a maze as quickly as mice without A-beta oligomers. Such oligomers prevent cross-talk between certain brain cells in the hippocampus of mice, which helps explain the loss of learning and memory functions in Alzheimer’s disease. © Society for Science & the Public 2000 - 2009

Old epidemic sheds new light on vCJD XAVIER BOSCH New evidence from an old epidemic could help those trying to estimate how many people may be incubating variant Creutzfeldt–Jakob disease (vCJD) - the human form of mad cow disease. So say scientists in the United States who have studied DNA extracted from victims of the first documented prion disease, kuru1. Like vCJD, kuru is a neurodegenerative disease caused by infection with a rogue 'prion' protein. The disease spread among the Fore people of Papua New Guinea in the 1940s and 1950s as a result of their cannibalistic funerary rituals. 1.Lee, H.-S. et al. Increased susceptibility to kuru of carriers of the PRNP 129 methionine/methionine genotype. Journal of Infectious Diseases 183, 192–196 (2001). © Macmillan Magazines Ltd 2001 - NATURE NEWS SERVICE Nature © Macmillan Publishers Ltd 2001 Reg. No. 785998 England.

CAMBRIDGE, Mass. – Scientists have discovered a new process for how memories might be stored, a finding that could help explain one of the least-understood activities of the brain. What's more, the key player in this process is a protein that acts just like a prion – a class of proteins that includes the deadly agents involved in neurodegenerative conditions such as mad cow disease. The study, published as two papers in the Dec. 26 issue of the journal Cell, suggests that this protein does its good work while in a prion state, contradicting a widely held belief that a protein that has prion activity is toxic or at least doesn't function properly. "For a while we've known quite a bit about how memory works, but we've had no clear concept of what the key storage device is," says Whitehead Institute for Biomedical Research Director Susan Lindquist, who coauthored the study with neurobiologist Eric Kandel at Columbia University. "This study suggests what the storage device might be – but it's such a surprising suggestion to find that a prion-like activity may be involved."

Research by North Carolina State University scientists, in conjunction with scientists from the Netherlands and BioResource International, an NC State spin-off biotechnology company, has shown that, under proper conditions, an enzyme can fully degrade the prion – or protein particle – believed to be responsible for mad cow disease and other related animal and human diseases. These transmissible prions – believed to be the cause of bovine spongiform encephalopathy (BSE), the technical name for mad cow disease, as well as the human and sheep versions, called Creutzfeldt-Jakob disease and scrapie, respectively – are highly resistant to degradation, says Dr. Jason Shih, professor of biotechnology and poultry science at NC State. But the new research, which tested the effects of a bacterial enzyme keratinase on brain tissues from cows with BSE and sheep with scrapie, showed that, when the tissue was pretreated and in the presence of a detergent, the enzyme fully degraded the prion, rendering it undetectable. The research was published in the Dec. 1 edition of The Journal of Infectious Diseases.

Study reveals antibodies can kill brain cells. HELEN PEARSON Antibody therapies designed to treat the human form of mad cow disease could backfire, warn US scientists. The group investigated the proteins called prions that cause the rare brain disorder variant Creutzfeldt–Jakob disease (vCJD) and its farmyard equivalent, bovine spongiform encephalopathy (BSE). Prions cause disease when they take on a misshapen form, accumulate in the brain and kill off nerve cells. Some research groups are trying to prevent this by using antibodies that grab hold of normal prions and prevent them from transforming into the harmful configuration. © Nature News Service / Macmillan Magazines Ltd 2003

Debora MacKenzie The infectious prions that cause Chronic Wasting Disease, an infection similar to BSE that afflicts North American deer and elk have been found in the parts of the animals that people eat. No one knows if CWD can jump to humans, but if it does hunters in affected areas might be at risk. CWD was first diagnosed as a spongiform encephalopathy in captive deer and elk in Colorado in the 1970s, and in wild deer and elk in the region in the 1980s. But in the 1990s it spread widely within the elk farming industry, jumped to wild deer, and now affects two provinces of Canada and 13 US states. Like the related sheep disease scrapie – though unlike BSE – CWD spreads from animal to animal, says Glenn Telling of the University of Kentucky at Lexington, US. Deer housed with infected animals, or fed infected brain experimentally, contract the disease. Because of this there are fears that the CWD prion might be distributed widely in the deer’s tissues – as scrapie is in sheep. Efforts to find the infectious prion in the muscle of infected animals, by seeing whether antibodies to the prion could find any and bind on, have previously failed. But Telling’s lab has now shown that diseased prions can reside in muscle of deer infected with CWD, by using transgenic mice. © Copyright Reed Business Information Ltd.

Stu Hutson The curative properties of stem cells may rely on prions, a new study suggests, the type of protein made infamous by mad cow disease. Prions are a special class of protein that can change the shape and function of other proteins around them. While these are found throughout any mammal’s body, the understanding of their biological role is limited. What is known is that prions that become misshapen, through some unknown process, can result in BSE (bovine spongiform encephalopathy) – mad cow disease – and its equivalents in other animals. Researchers at the Whitehead Institute in Cambridge, Massachusetts, US, have now found that adult stem cells in bone marrow gradually lose their ability to regenerate without their normal complement of membrane-bound prions. Stem cells are primitive cells which have the potential to divide endlessly, and the ability to differentiate into any cell type in the body – offering hope for future therapies. Andrew Steele, Cheng Cheng Zhang and colleagues used radiation to deplete the bone marrow of mice genetically engineered to not produce the prion proteins. The animals’ marrow regenerated quickly at first, but eventually slowed to a stop. The marrow also lost its regenerative abilities when transplanted into normal mice. © Copyright Reed Business Information Ltd

Debora McKenzie Viruses, not prions, may be at the root of diseases such as scrapie, BSE and variant Creutzfeldt-Jakob disease (vCJD), researchers say. If true, the new theory could revolutionise our understanding of these so-called transmissible spongiform encephalopathies (TSEs), and potentially lead to new ways of treating them. The widely accepted theory of what causes infectious prion diseases – such as vCJD, scrapie and “mad cow disease” – is that deformed proteins called prions corrupt other brain proteins, eventually clogging and destroying brain cells. However, this theory has not been definitively proven. Laura Manuelidis at Yale University in New Haven, Connecticut, US, has insisted for years that tiny virus-like particles observed in TSE-infected brains may be the culprits. But such brains are degenerating, so the particles had been dismissed as general debris. When Manuelidis studied cultures of neural cells infected with two particular strains of scrapie and CJD, she found that these virus-like particles were clustered in regular arrays within the cells – in a pattern that viruses regularly form in cells – and she saw no apparent prions in the cells. © Copyright Reed Business Information Ltd.

Prions, the mis-folded proteins best known for causing diseases such as bovine spongiform encephalopathy in cows, scrapie in sheep and Creutzfeldt–Jakob disease in humans, could also help yeast survival, according to a study in the journal Cell1. "We think prions are really important," says co-author Simon Alberti of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. "When environmental conditions are harsh, they might allow a species to survive." The work, led by Susan Lindquist of the Whitehead Institute, bolsters the theory that prions might confer an evolutionary advantage, says Alberti. Lindquist first broached that idea nine years ago, after finding that a prion called PSI+ in the yeast Saccharomyces cerevisiae triggered heritable changes that could provide a way of adapting to fluctuating environments2. More recent work also suggests prions might play a role in memory in sea slugs and smell in mice. In the new work, a scan of the S. cerevisiae genome yielded 24 potential prion-forming proteins. Only five prions were known to exist in yeast before this study. The team focused on a protein called Mot3 and found that it can twist into a prion form. When in its normal shape, Mot3 suppresses yeast genes involved in building the cellular wall. But when Mot3 kinks into a prion, it loses this function and the wall-building genes activate. Hence, yeast carrying the Mot3 prions grew thicker, more robust cell walls. © 2009 Nature Publishing Group,

Jim Schnabel Of all the ways that proteins can go bad, becoming an amyloid is surely one of the worst. In this state, sticky elements within proteins emerge and seed the growth of sometimes deadly fibrils. Amyloids riddle the brain in Alzheimer's disease and Creutzfeldt–Jakob disease. But until recently it has seemed that this corrupt state could threaten only a tiny fraction of proteins. Research is now hinting at a more unsettling picture. In work reported in February, a team led by David Eisenberg at the University of California, Los Angeles, sifted through tens of thousands of proteins looking for segments with the peculiar stickiness needed to form amyloid1. They found, says Eisenberg, that "effectively all complex proteins have these short segments that, if exposed and flexible enough, are capable of triggering amyloid formation". Not all proteins form amyloids, however. The 'amylome', as Eisenberg calls it, is restricted because most proteins hide these sticky segments out of harm's way or otherwise keep their stickiness under control. His results and other work suggest that evolution treats amyloids as a fundamental threat. Amyloids have been found in some of the most common age-related diseases, and there is evidence that ageing itself makes some amyloid accumulation inevitable. It now seems as though the human body is perched precariously above an amyloidal abyss. "The amyloid state is more like the default state of a protein, and in the absence of specific protective mechanisms, many of our proteins could fall into it," says Chris Dobson, a structural biologist at the University of Cambridge, UK. © 2010 Nature Publishing Group,

Experts offer some advice on deer illness By BRIAN TUMULTY Press-Gazette Washington bureau WASHINGTON — Scientists and wildlife experts testifying at a congressional hearing Thursday acknowledged there are many unanswered questions about the always fatal chronic wasting disease that has infected deer and elk in eight states ranging from Colorado to Wisconsin. But they did offer some basic advice for the public: Q. How likely is it that people may become infected? A. It’s highly unlikely. “There’s no evidence that chronic wasting disease poses a threat to humans,” said Russell George, director of the division of wildlife at the Colorado Department of Natural Resources. Q. What does the disease do? A. Animals become emaciated or “wasted” by chronic weight loss. Chronic wasting disease, or CWD as it is often called, is always fatal. But it usually takes 16 to 32 months to incubate. Animals often become listless, lower their heads and walk in repetitive patterns. Some infected elk become highly excited and nervous. Q. Is the disease a virus or bacteria? A. Neither. CWD is a form of protein, according to wildlife veterinarian Michael Miller of the Colorado Department of Natural Resources. It is scientifically described as a transmissible spongiform encephalopathy or TSE. Once an animal is infected, the toxicity builds until the animal dies. Copyright © 2002

By SANDRA BLAKESLEE DENVER, — Wildlife experts from the United States and Canada are meeting here to discuss strategies for containing the spread of chronic wasting disease, the variant of mad cow disease that kills deer and elk. The malady, once found only in the brushy foothills near Fort Collins, Colo., has now been identified in both captive and wild herds of deer and elk in Kansas, Montana, Nebraska, New Mexico, Oklahoma, South Dakota, Wisconsin and Wyoming and the Canadian provinces of Saskatchewan and Alberta. Some states, like New Mexico, have found only one infected animal in the wild. But Saskatchewan, for example, has diagnosed the disease in more than 100 captive animals bred for their meat and antlers. Copyright 2002 The New York Times Company

Researchers puzzle over brain illness in North American wildlife Susan Milius This autumn, the nation's big-game hunters are lifting their guns and bows in the service of science. They're collecting the biggest sample ever of deer and elk brains—predicted to total 200,000—to test for a once-obscure wildlife disease that's become the stuff of headlines and headaches coast-to-coast. So-called chronic wasting disease strikes mule deer, white-tailed deer, and elk. It riddles the brain with tiny holes as the victim slowly withers and dies. Once found in the wild only in an area intersecting Colorado, Wyoming, and Nebraska, the disease appears to be spreading. This year, it turned up in wild herds in South Dakota, New Mexico, and Canada and jumped all the way to Wisconsin and Illinois. This disease belongs to the same class of maladies as mad cow disease, which appeared in Britain in 1986 and about a decade later, showed up in people who had eaten tainted meat. Last year, some 11 million people hunted deer and elk in the United States, and many more helped them eat their prizes. So far, the news for hunters looks reassuring. Several weighty groups, including a panel from the World Health Organization, have concluded that there's no evidence so far that people can catch chronic wasting disease. From Science News, Vol. 162, No. 22, Nov. 30, 2002, p. 346. Copyright ©2002 Science Service. All rights reserved.

— Howard Hughes Medical Institute researchers have found that a gene mutation that produces a black coat color in mice also causes degeneration of neurons similar to that observed in prion-caused diseases, such as Creutzfeldt-Jakob disease and “mad cow disease.” The scientists say that their findings could improve understanding of how the renegade proteins, called prions, destroy the brains of infected humans, cattle and sheep. In an article published in the January 31, 2003, issue of the journal Science, researchers led by Howard Hughes Medical Institute investigator Gregory Barsh reported that a gene mutation in mahoganoid mice causes neural damage that closely resembles that observed in spongiform encephalopathies. The work was carried out by Lin He and Teresa Gunn, graduate student and former postdoctoral fellow with Barsh, respectively, and also involved collaboration with the University of Michigan School of Medicine. Gunn, He, and Barsh began looking at the effects of mahoganoid mutation on neural development after their studies of another mutation in a similar coat-color gene, called Attractin, turned up some intriguing results. ©2003 Howard Hughes Medical Institute

By NICHOLAS WADE Deep in the recesses of the human heart, lurking guiltily beneath the threshold of consciousness, there may lie a depraved craving — for the forbidden taste of human flesh. The basis for this morbid accusation, made by a team of researchers in London, is a genetic signature, found almost worldwide, that points to a long history of cannibalism. The signature is one that protects the bearer from infection by prions, proteins that can be transmitted in infected meat and attack the nerve cells of the brain. Prions can be acquired from eating infected animals, as in the case of the mad cow disease that in 1996 spread to people in England, but they spread even more easily through eating infected humans. This fact is known from study of the Fore, a tribe in the eastern highlands of Papua New Guinea that started to practice ritual cannibalism at the end of the 19th century. Dr. D. Carleton Gajdusek, who later received a Nobel Prize for his work, noticed that the Fore were being devastated by a neurodegenerative disease known as kuru. He linked it with their practice of eating the brains of their dead in mortuary feasts. When the feasts were banned by Australian authorities in the mid-1950's, the incidence of kuru declined, and no cases have appeared in anyone born after that time. Copyright 2003 The New York Times Company

By CLIFFORD KRAUSS with SANDRA BLAKESLEE VANCOUVER, British Columbia, — Mad cow disease was diagnosed in a cow in Canada today, and United States health authorities immediately placed a ban on imports of beef, cattle and animal feed from Canada. The report shocked ranchers through much of western Canada, where trading in livestock was immediately halted because of plummeting cattle prices. The shock waves spread through the financial markets, where prices in many Canadian and American meat and restaurant companies fell sharply. Canadian authorities stressed that only one cow out of Canada's total cattle population of 3.6 million was found to be sick and there was no immediate evidence that the disease had spread among livestock or humans. Copyright 2003 The New York Times Company

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