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Iron is involved in prion disease-associated neuronal demise
March 16, 2009Imbalance of iron homeostasis is a common feature of prion disease-affected human, mouse, and hamster brains, according to a new study by Dr. Neena Singh and colleagues at Case Western Reserve University School of Medicine, alongside collaborators from Creighton University. These findings, published March 13 in the open-access journal PLoS Pathogens, provide new insight into the mechanism of neurotoxicity in prion disorders, and novel avenues for the development of therapeutic strategies.
Unlike other neurodegenerative conditions, prion disorders are sporadic, inherited, and infectious, and affect both humans and animals; common examples are mad cow disease in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease in humans. The causative agent is a misfolded protein referred to as PrP-scrapie that replicates itself by changing the conformation of neighboring copies of the same protein, namely the prion protein. Aggregates of PrP-scrapie are toxic to brain cells and cause a spongy-like appearance in diseased brains.
Research from the Singh laboratory suggests that accumulation of PrP-scrapie alters the metabolism of iron in diseased brains. The imbalance of brain iron homeostasis worsens with disease progression, and is not an outcome of end-stage disease. Since iron is highly toxic when mismanaged, this condition is likely to contribute significantly to prion-disease-associated neurotoxicity. The likely cause of this condition is loss of normal function of the prion protein in cellular iron metabolism demonstrated recently by Singh and colleagues, combined with gain of toxic function by the redox-active PrP-scrapie complex as shown in this report.
Singh and her team were surprised to find that prion disease-affected brains are iron deficient despite a significant increase in their overall iron content. The group concludes that ferritin, a major iron storage protein, co-aggregates with PrP-scrapie in diseased brains and sequesters bound iron in the complex, creating a state of apparent iron deficiency. The brain cells respond to this condition by increasing their level of iron uptake, thus creating a vicious cycle of increased iron uptake in the presence of increased iron.
These observations contribute to our understanding of how the prion agent causes neurotoxicity, and may enable the development of novel therapeutic strategies targeted at restoring brain iron homeostasis in prion disorders.
http://dx.plos.org/10.1371/journal.ppat.1000336
Singh and her team were surprised to find that prion disease-affected brains are iron deficient despite a significant increase in their overall iron content. The group concludes that ferritin, a major iron storage protein, co-aggregates with PrP-scrapie in diseased brains and sequesters bound iron in the complex, creating a state of apparent iron deficiency. The brain cells respond to this condition by increasing their level of iron uptake, thus creating a vicious cycle of increased iron uptake in the presence of increased iron.
These observations contribute to our understanding of how the prion agent causes neurotoxicity, and may enable the development of novel therapeutic strategies targeted at restoring brain iron homeostasis in prion disorders.
http://dx.plos.org/10.1371/journal.ppat.1000336
Prion Current Events and Prion News RSSPrion study reveals first direct information about the protein's molecular structure
A collaboration between scientists at Vanderbilt University and the University of California, San Francisco has led to the first direct information about the molecular structure of prions.
U of T led research team uncovers evolutionary origins of prion disease gene
A University of Toronto-led team has uncovered the evolutionary ancestry of the prion gene, which may reveal new understandings of how the prion protein causes diseases such as bovine spongiform encephalopathy (BSE), also known as "mad cow disease."
Species barrier may protect macaques from chronic wasting disease
Data from an ongoing multi-year study suggest that people who consume deer and elk with chronic wasting disease (CWD) may be protected from infection by an inability of the CWD infectious agent to spread to people.
A Penny for Your Prions
North Carolina State University researchers have discovered a link between copper and the normal functioning of prion proteins, which are associated with transmissible spongiform encephalopathy diseases such as Cruetzfeldt-Jakob in humans or "mad cow" disease in cattle.
Scripps Florida scientists devise accelerated method to determine infectious prion strainsScripps Florida scientists devise accelerated method to determine infectious prion strains
Current tests to identify specific strains of infectious prions, which cause a range of transmissible diseases (such as mad cow) in animals and humans, can take anywhere from six months to a year to yield results - a time-lag that may put human populations at risk.
Prevalence of variant CJD agent in Britain remains uncertain
First results from a large tissue survey in Britain of the agent that causes variant Creutzfeldt-Jakob disease (vCJD) are unable so far to establish that the prevalence is lower than that given by previous estimates, concludes a study published on bmj.com today.
Redefining what it means to be a prion
Whitehead Institute researchers have quintupled the number of identifiable prion proteins in yeast and have further clarified the role prions play in the inheritance of both beneficial and detrimental traits.
Prion discovery gives clue to control of mass gene expression
The discovery in common brewer's yeast of a new, infectious, misfolded protein -- or prion -- by University of Illinois at Chicago molecular biologists raises new questions about the roles played by these curious molecules, often associated with degenerative brain diseases like "mad cow" and its human counterpart, Creutzfeldt-Jakob.
Antibody key to treating variant CJD, scientists find
Scientists at the University of Liverpool have determined the atomic structure of the 'binding' between a brain protein and an antibody that could be key to treating patients with diseases such as variant CJD.
Self-regulating molecular 'transformers' control intracellular protein delivery
Scientists from the California Institute of Technology (Caltech) have uncovered the Transformer like properties of molecules responsible for carrying and depositing proteins to their correct locations within cells.
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The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases by Philip Yam (Author) In 1996, British doctors were horrified to discover that mad cow disease (BSE), an affliction that had been plaguing British cattle for ten years, had jumped the species barrier and was appearing in humans as variant Creutzfeldt-Jakob disease (vCJD). Not unlike the mad cows, victims of vCJD suffer from a degenerative neurological disease that peppers the brain with microscopic holes, causing dementia, loss of motor control, and certain death. What alarms researchers and public health officials worldwide is that the incubation period for vCJD may be as long as 10 or even 15 years, and during this period those infected are symptom-free. And because the disease is so far undetectable except by autopsy, there is no way of knowing with certainty how many people have already been infected. In... |
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The Family That Couldn't Sleep: A Medical Mystery by D.T. Max (Author) 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 raw before collapsing. In England, cows attack their owners in the milking parlors, while in the American West, thousands of deer starve to death in fields full of grass. What these strange conditions–including fatal familial insomnia, kuru, scrapie, and mad cow disease–share is their cause: prions. Prions are ordinary proteins that sometimes go wrong, resulting in neurological... |
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Prion Biology and Diseases, Second Edition (Cold Spring Harbor Monograph Series) by Stanley B. Prusiner (Author), Stanley B. Prusiner (Editor) A new edition of the most authoritative book in its field, first published in 1999 and edited by the Nobel Prize–winning founder of the field. This edition is expanded and completely updated, and includes chapters on therapeutics, and diagnostic methods and approaches. |
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Prion Defiance (Primary Contributor) |
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