The Deadly Mystery of Prions

Deer that became zombies

zomDeer in at least 22 U.S. states and parts of Canada have died from a neurological disease called “chronic wasting disease,” according to the Centers for Disease Control and Prevention (CDC). Authorities are concerned that this illness, which is sometimes dubbed “zombie deer disease,” might spread to people, just as “mad cow disease” has done in the past.
Chronic wasting disease can cause a number of symptoms in animals, including drastic weight loss, a lack of coordination, drooling, listlessness or a “blank” facial expression, and a lack of fear of people, according to the CDC. It infects members of the deer (cervid) family, including white-tailed deer, mule deer, reindeer, moose and elk.
The disease was first discovered in Colorado in 1967, according to the CDC, and so far, no cases in humans have ever been reported.
Indeed, the infectious proteins that cause chronic wasting disease — called prions — don’t easily jump between species, said Mark Zabel, associate director of the Prion Research Center at Colorado State University. But it’s known that these proteins can evolve to infect other species, Zabel said. For example, the type of prion that causes so-called bovine spongiform encephalopathy, or “mad cow disease,” was transmitted to people who ate infected meat (mostly in the United Kingdom in the 1980s and ’90s), resulting in several hundred human infections.
“We have every reason to suspect” that chronic wasting disease could pass to humans, Zabel told Live Science. The disease “may still be evolving, and it may be just a matter of time before a prion evolves in a deer or elk that is capable of infecting a human, he said.” [10 Deadly Diseases That Hopped Across Species]


Recently, researchers in Canada raised concerns about the possibility that the disease could jump to humans, after a study showed that macaque monkeys could get the disease from eating infected meat. Out of five monkeys that were fed infected white-tailed-deer meat, three tested positive for chronic wasting disease, according to The Tyee, a Canadian news outlet. This is the first time that the disease has been found to spread to primates through the consumption of infected meat, according to the Associated Press.
Infectious prions cause disease when they start to fold abnormally and trigger the misfolding of other, similar proteins. Studies by Zabel’s lab and others have shown that the prion proteins that cause chronic wasting disease are “flexible,” meaning they can “adopt many different shapes relatively easily,” Zabel said.
Moreover, some studies have shown that researchers can artificially evolve the prions that cause chronic wasting disease (either in a test tube or animal models) so that the altered prion proteins can cause human proteins to misfold, Zabel said.
This suggests that if chronic-wasting-disease prions evolve in nature, they could potentially cross the species barrier, he said.

The mystery of prions

A number of fatal neurodegenerative diseases in humans–such as Creutzfeldt-Jakob disease (CJD), kuru and Gerstmann-Straussler-Scheinker (GSS) disease–are thought to be caused by a mysterious infectious agent known as a prion. Prions also cause disease in a wide variety of other animals, including scrapie in sheep and bovine spongiform encephalopathy (BSE) in cows.

Just, what are prions and how do they cause disease?

Prions are proteins that have changed their normal shape. Proteins are the building blocks of living cells that are used by our bodies either as structural elements or as signaling molecules that carry information throughout our body. They consist of chains of amino acids folded into complex shapes. When the shape of a protein changes the spectrum of waves it is emitting changes. The prion protein is now transmitting a different informational message into your body. In effect, your body is now tuned to a new radio station and instead of classical music you may be getting hard-rock. When the prion creates a “disease” in the body it is known as a “mutant prion” since it can start a chain reaction and persuade other proteins to follow its example. That process can spread the disease through the cells and eventually to the brain. Just as we have “informational medicine” like homeopathy that can be used to heal us, we now have “informational disease” that can kill us.

Western science, and therefore our approach to the way in which we handle our food supply, has been confronted with an informational disease — mad-cow disease. The phenomenon was not a part of classical biochemistry and was only officially recognized in 1997 when Dr. Stanley Prusiner of UCSF won the Nobel Prize in Medicine for “his pioneering discovery of an entirely new genre of disease-causing agents.” Dr. Prusiner had discovered that altered versions of proteins, which he dubbed prions, are to blame for a family of human and animal diseases. Prusiner had pursued his specific area of research since 1972 but was met with incredulity, criticism, and controversy. Unlike bacteria, virus, or parasites, an “infectious” prion cannot be destroyed by heat, freezing or radiation. For example, to destroy mutant-prion infected meat the USDA facility at Ames, Iowa uses a tissue digestor, a large stainless steel vat that melts the carcasses in boiling lye under pressure, then dries the liquid into a powder that is incinerated.

Initially, mad-cow disease was a scientist’s worst nightmare since no one knew how it was transmitted. Early estimates were that millions of people in the United Kingdom could get the brain-wasting degenerative disease. Even through in the United Kingdom more than 185,000 cattle were found to be infected, only 143 cases of the always-fatal human version of the disease have been diagnosed. The number of new human cases has now leveled off at fewer than 20 a year. Only 10 people outside of the United Kingdom are known to have died from the human form of the disease. One cause for the low death rate could be the body’s quality control system for handling misfolded proteins. When a cell detects such prions it sends a signal to the nucleus to activate a program to destroy these mistakes. However, a disturbing note is that Britain, on Dec. 17, 2003, reported the first case of a person dying after a blood transfusion from an infected donor.


Mad cow disease

Glow in cattle’s eyes may be a sign of mad cow disease

Mad-cow disease, officially known as bovine spongiform encephalopathy (BSE) was first diagnosed in 1986 in Britain. Researchers quickly decided that cattle had gotten the disease from eating brains and nerve tissue of sheep infected with scrapie a variant of mad-cow disease. The tissues had been mixed into cattle feed along with the ground-up carcasses of other animals – including other cows. Such “rendered” feed has now been banned for most food animals. Today Japan tests every cow that enters the food supply for BSE, and Europe tests every animal older than 30 months (the age at which the incidence of BSE starts to climb). However, currently in the United States only about 20,000 of the 35 m5 million cattle slaughtered each year are tested for BSE, i.e., an insignificant 0.06% are tested.

If BSE is an “informational” disease than there should be other variations. We know that mad-cow disease can be caused by a mutation of a single gene, a so-called spontaneous case. Similar spongy-brain diseases have also appeared in at least 10 animal species. Included are farmed mink, domestic cats, cougars, bison, and African antelope (kudu & oryx). The so-called chronic wasting disease also strikes mule deer, white-tailed deer, and elk in the wild. Sheep carry a variant of mad-cow disease known as scrapie. Shepherds and pathologists have recognized it since the 18th century. Sheep haven’t been known to transmit their brain disease to people despite centuries of opportunity. In fact, potted sheep’s brain is a national dish in Scotland. This has raised questions about current theories regarding the scrapie as the trigger of BSE in Britain.

Is there maybe another underlying cause for these diseases, and the unparalleled large surge of mad-cow disease in the United Kingdom?

The link to food supply and heritage factors

An organic farmer, Mark Purdey, and a number of researches are putting forth an

hypothesis based upon environmental causal factors. They implicate a warble fly eradication program mandated in the early 1980s by the British government. Warble flies lay their eggs in a cow’s skin, causing health problems and reducing the value of cow hides. To combat this heavy doses of organophosphate insecticides were used. These were poured along the spinal column of cows to be absorbed into the cow’s body. They exert their toxic effect by entering the central nervous system and deforming the molecular shape of various nerve proteins. Organophosphates were developed by Nazi chemists during the course of World War II as a biological weapon. The effects of organophosphates can be made more severe because they remove copper from the body leaving the door open for manganese or similar metals to replace the copper in the prion protein. This creates a condition akin to the occupational disease known as “Manganese Madness.” The “informational” disease caused in humans by BSE is called variant Crueutzfeldt-Jakob Disease (vCJD)s. In addition to CJD and vCJD, could other degenerative ailments in humans, such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease involve abnormal changes in the shapes of proteins caused by environmental factors that affect us directly or indirectly via our food supply?
“Confusingly, researchers also recognized that some prion diseases, such as GSS, were inherited. The pattern of inheritance was recognized as being autosomal and dominant, meaning that if a parent developed GSS, there was a 50 percent chance that a child of either sex would also develop the disease. Any explanation for the cause of a prion disease therefore has to account for random, inherited and transmitted variants of the disease.
“Although there is not yet a universally accepted explanation of this puzzle, progress is being made. We now know that a normal cellular protein, called PrP ( for proteinaceous infectious particle) and which is found in all of us, is centrally involved in the spread of prion diseases. This protein consists of about 250 amino acids.
“Some researchers believe that the prions are formed when PrP associates with a foreign pathogenic nucleic acid. This is called the virino hypothesis. (Viruses consist of proteins and nucleic acids that are specified by the virus genome. A virino would also consist of proteins and nucleic acids, but the protein component is specified by the host genome, not the pathogen genome). In support of the virino hypothesis is the existence of different strains of prions that cause differing patterns of disease and breed true; the existence of strains in pathogens is usually the result of changes in the nucleic acid sequence of the infectious agent. Scientists have not found any nucleic acid associated with a prion, however, despite intensive efforts in many laboratories. Furthermore, prions appear to remain infectious even after being exposed to treatments that destroy nucleic acids.
“This evidence has led to the now widely accepted prion theory, which states that the cellular protein PrP is the sole causative agent of prion diseases; there is no nucleic acid involved. The theory holds that PrP is normally in a stable shape (pN) that does not cause disease. The protein can be flipped, however, into an abnormal shape (pD) that does cause disease. pD is infectious because it can associate with pN and convert it to pD, in an exponential process–each pD can convert more pN to pD.
“Prions can be transmitted, possibly by eating and certainly by inoculation either directly into the brain or into skin and muscle tissue. Exponential amplification of the prion (converting pN into pD in the body) would then result in disease. Occasional, sporadic cases of prion diseases arise in middle or old age, presumably because there is a very small but real chance that pN can spontaneously flip to pD; the cumulative likelihood of such a flip grows over the years. Inherited cases of CJD and GSS may result from mutations in the PrP gene, which gives rise to changes in the amino acid sequence of the PrP protein. This change would increase the probability of pN transforming into pD, so that the disease would almost certainly occur.

Scientific Research

300px-R7_prion“Physical analysis of the structure of PrP provides some direct evidence for the existence of two different (normal and aberrant) shapes. Recently the structure of the core part of the PrP protein was determined by magnetic resonance image analysis. Mutations that cause prion disease are clustered within or adjacent to key structural elements in the protein, so it is easy to imagine that mutations destabilize the structure of pN and cause it to reconfigure into pD.
“The prion theory has not been proved correct, but much evidence now supports it. We do not yet know why the pD structure of a prion would result in neurodegeneration, but we do know that prion protein accumulates in brain tissue. One part of the prion protein can cause apoptosis, or programmed cell death; perhaps this mechanism explains the pattern of the disease.
“Prions have long intrigued scientists because of their unusual properties. Recently the general public has become interested in them as well because of the epidemic of BSE, more dramatically known as mad cow disease. Hundreds of thousands of infected animals have been eaten by Europeans and particularly the British over the past 10 years. The latest research suggests that the infected meat may pose a threat to human health, but the significance of that threat may not become apparent for years. Although it is generally considered a British problem, BSE is almost certainly a natural disease of cattle, so it is undoubtedly found in other countries as well. The normal incidence of BSE is vanishingly small, however. The U.S. Department of Agriculture claims that BSE has not been identified in any U.S. cattle.

Could Alzheimer’s and Parkinson’s be infectious?

The archetypal prion-based disease is kuru, which spread through cannibalistic rituals in the Eastern Highlands of Papua New Guinea.

Kuru affected mostly women and children of the Fore tribe, who ate brains and spinal cords of deceased relatives, and subsequently developed body tremors, balance problems and slurred speech. There’s no cure for kuru and sufferers always died. But it no longer strikes as cannibalism in the region has been eliminated.
Other prion diseases include scrapie in sheep and goats and bovine spongiform encephalopathy (BSE) in cows. When transmitted to humans during the “mad cow disease” outbreak in Europe, BSE resulted in variant CJD (vCJD).
The newly described addition to the prion disease canon, Shy-Drager syndrome (SDS) or multiple system atrophy (MSA), was first recognised in the early 1960s and has many features in common with Parkinson’s disease.
The most important of these is that a protein known as α-synuclein (α-syn) accumulates in the brain, in both Parkinson’s and SDS/MSA. This accumulation is very similar to what happens in CJD, where the prion protein (PrP) accumulates, and also in Alzheimer’s disease and other dementias, where two types of proteins, known as amyloid beta (Aβ-amyloid) and tau, build up in the brain.


Infected with prions, the brain of a vCJD victim reveals spongy areas (yellow).

The clumps and tangles of these various aggregated proteins cause neurons to degenerate and die. This is a cumulative process which takes between months and decades to manifest as overt disease.
In fact, many of the neurodegenerative diseases of the ageing brain are associated with the accumulation and deposition of specific proteins. It has long been suspected that neurodegenerative diseases in general may all ultimately be caused by this process of proteins getting caught in the wrong process, and misfolding.
This misfolding sets off a cascade of events: the proteins oligomerise (a number of identical molecules join together); accumulate; nucleate (form a nucleus or centre); polymerise (combine to build a structure with its components); self-replicate; and eventually, propagate and spread throughout the brain. Many of these protein changes also occur in the usual food cooking process (aggregation of proteins caused by heating) or food preparation (the solidification of proteins in the refrigerator).
Finally, some but not all of these misfolded proteins gain the ability to be transmitted between people and animals. In fact, the word “prion” was coined by Prusiner in 1982 to describe this property of a pro_teinaceous in_fectious particle. And we don’t yet know of ways to easily “dis-infect” or kill these proteins. All kinds of chemicals that kill bacteria and viruses do not harm prions.
Infectious Proteins
Scientists have always kept – and still do – an open mind about whether Alzheimer’s disease and other neurodegenerative conditions are transmissible. We’ve known since the early 1960s that amyloid fibrils – the accumulations of Aβ-amyloid in the brain – are self-propagating entities.
In diseases involving amyloid protein, the “amyloid enhancing factor”, which causes the disease to progress, is thought to be amyloid itself. In other words, the amyloid is self-replicating and makes copies of itself exponentially.

We know that the Alzheimer’s disease-causing human Aβ-amyloid can cross-seed Aβ-amyloid accumulation in genetically susceptible rodents. Mice carrying an unstable and genetically modified human protein can then be “infected” by giving them a dose of the human abnormal protein. But there’s still no direct evidence that Alzheimer’s disease is transmissible between people.
Working out whether SDS/MSA is transmissible, at least from humans to genetically susceptible transgenic cell and rodents, is the first step in testing if it’s transmissible from humans to primates, or indeed among people.
As a precautionary measure, the authors of the paper warn we should now take additional safety precautions in the neurosurgical clinics where deep brain stimulation is used to control the tremors caused by Parkinson’s disease. Because of the overlap in symptoms and signs of Parkinson’s with SDS/MSA, it’s likely that some people with the newly described disease have been treated by deep brain stimulation.
It’s important to ensure that cross-contamination of neurosurgical equipment doesn’t occur because we don’t want to inadvertently transmit a disease between humans. Using disposable stimulation electrodes, for instance, will be mandatory in the future. Similar concerns have already been raised about other neurodegenerative illnesses, such as diseases involving misfolded tau protein, which cause frontotemporal dementia.
With the publication of this paper, the spectrum of prion diseases has been enlarged, perhaps considerably. But until it becomes possible to evaluate the role of intra-species transmission, SDS/MSA will have to remain in the category of “hypothetically transmissible to a genetically susceptible recipient”.
It’s premature to classify it as being the same as CJD, which is clearly transmissible within and between species. That has been made apparent by the mad cow saga, which still has years to run due to the long latency from prion infection to overt disease.

The impact on the future


Some have come up with the idea that on a long term view, the existence of prions and their devastating consequences in living organisms together with their way of transmission will definitely change human nutrition habits.
“Science is trying to find a prevention and a solution for the phenomenon of prions”, says Dr. Peter Weiler, who was formerly teaching at the German university in Potsdam. “However, they come in a variety of forms and spread in a way that doesn’t follow any known pattern. Always more species are being discovered to develop prion-based disease. Meat-eating from animals that were once alive might become a deadly danger one day – or a luxury not affordable for everybody.”
So will meat-eaters soon have to give up on their preferred dishes?
Weiler thinks that meat will be created from cell cultures on day.
“Nature won’t be able to cope with the current habits of a human population that increases at such a high rate,” he says.
To the question whether prions might be the answer of nature to human behavior, we only receive an enigmatic smile.



Foundation for Mind-being Research

American Scientific

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