Could a virus produce prions, leading to prion disease?

Could a virus produce prions, leading to prion disease?

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Viruses can make cells produce proteins that are not a part of the new viruses themselves, but are used to help with replication. However in the case of rotavirus, one of these proteins (NSP4) is actually a toxin that causes diarrhoea. Prion diseases like Creutzfeldt-Jakob disease are caused by misfolded proteins that make normal versions of the protein also misfold, causing a chain reaction.

While this might not actually have been observed in real life, is there a biological basis for a virus containing genetic code for producing a prion, that after infecting an organism will cause the production of prions inside of infected cells (or perhaps proteins that cause the production of prions in the body), leading to a prion disease - in a similar way to how rotavirus causes the production the the NSP4 toxin? Since these prion diseases often have 100% fatality, would this mean a virus like the common cold could arise, that spreads quickly and non-fatally, but then triggers a fatal neurodegenerative disease in its victims by causing the production of prions in the host?

Perhaps not prions themselves, but viruses may possibly contain "pieces" or domains of proteins with prion-like chemical activity, which can catalyse refolding of prions from normal to disease state.

Mutation rates put limits on the size of RNA viruses. There is a higher cost for the average RNA virus to allot precious genomic space on encoding a normal protein that would take decades to be pathogenic, and which does not seem to help make copies of the virus.

Because DNA is a more stable molecule, and DNA polymerase has a higher fidelity rate than RNA polymerase, DNA viruses can have a larger genome. They could more easily carry code for encoding prion-like domains inside proteins.

There's a recent paper from George and Victor Tetz that looks for these so-called "prionogenic domains" (regions which encode portions of another protein that could potentially have prion-like behavior) in a catalog of viral genomes, and they find approximately three times more such domains in DNA viruses than in RNA viruses:

We determined that more PrDs can be found in the DNA-viruses compared with their numbers in the RNA-viruses, and in the enveloped viruses, compared with that in the non-enveloped ones. This may be partially explained by the larger genome size and protein numbers in DNA-viruses.

While the domains themselves are usually part of proteins that are not themselves prions, infection could lead to expression of those proteins, which in turn provides the domain templates that invoke misfolding in the host of normal prions into pathogenic (disease-causing) prions:

Some viruses may be implicated in the prion misfolding in humans since it was observed that the de novo appearance of prions can be facilitated by another PrD-containing protein

Also! There are retroviruses that have integrated themselves in our genome over millions of years. These are called "endogenous retroviruses" or ERVs, and have been called "junk DNA" by some biologists. However, some get expressed along with our normal genes:

Although a large percentage of ERVs are replication-defective or are suppressed by host defense mechanisms, some ERVs can be expressed and replicated. The activation of an ERV gene can bring positive co-opted functions to the host, which may be evolutionarily maintained [13,20]. For instance, some ERV proteins may provide important functions during normal development; for example, human protein syncytine-1, which is an ERV Env protein, is involved in the formation of the syncytial layer in the placenta [30,31]. Moreover, the expression of Env proteins encoded by ERVs has been suggested to mediate host resistance to exogenous pathogens [32,33]. However, because of their analogy to exogenous retroviruses, the activation of certain ERVs has been frequently implicated in disease.

The authors observed that some people who develop Creutzfeldt-Jakob disease (CJD) have ERVs that get overexpressed:

To evaluate the possible relationship between HERVs and human prion disease, we examined the retroviral sequences in cerebrospinal fluid (CSF) obtained from individuals with sporadic CJD. The frequencies of several HERV families, including HERV-W, HERV-L, FRD and ERV-9, were significantly increased in the CSF of individuals with sporadic CJD compared to the frequencies observed in normal control CSF. In addition, when compared to individuals with other neurodegenerative diseases that exhibit similar symptoms to CJD, such as dementia, the incidence rate of HERV-W and HERV-L were significantly higher in the CSF of sporadic CJD patients. Moreover, the frequency of increased HERV-W and HERV-L in the same samples was much higher in sporadic CJD than in either normal or other neurodegenerative diseases CSF samples, and there was no correlation between individual parameters, such as sex and age [61].

The cause may not be expression of proteins with PrD, but with the triggering of signaling pathways that lead to inflammation of tissues, which sets up conditions for normal prions to malform into disease-causing prions:

According to these studies, ERV proteins may be closely implicated in the pathogenesis of inflammatory diseases, such as multiple sclerosis and rheumatoid arthritis (RA) [51,54,68]. In prion diseases, a correlation between the inflammatory process and neurodegeneration has been suggested because of the activation of large numbers of glial cells and the up-regulated expression of proinflammatory cytokines, which are pathological features of prion diseases [69,70].

Life is complicated.

Virus in the frame for prion diseases

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.


How Prions Came to Be: A Brief History

The origins of scrapie are unknown. Perhaps sheep have always been afflicted by the illness in low numbers, and the disease simply went unnoticed by human herders. What is understood with greater certainty is that incidences of scrapie were recorded during the 18th and 19th centuries when the exportation of sheep from Spain coincided with an increased occurrence of scrapie. Furthermore, inbreeding sheep to improve wool quality, a practice encouraged by economic incentives, also increased the prevalence of scrapie 33 . When inbreeding ceased, scrapie levels simultaneously fell. The following 1759 document from Germany describes the disease 33 :

Some sheep also suffer from scrapie, which can be identified by the fact that affected animals lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame. They drag themselves along, gradually become emaciated and die. Scrapie is incurable. The best solution, therefore, is for a shepherd who notices that one of his animals is suffering from scrapie, to dispose of it quickly and slaughter it away from the manorial lands for consumption by the servants of the nobleman. A shepherd must isolate such an animal from healthy stock immediately because it is infectious and can cause serious harm to the flock 34 .

Based on this passage, one can conclude that scrapie is infectious in sheep, but not in the human servants eating the diseased animals 33 . So far, these conclusions have proven accurate (remember that all cases of vCJD in Britain were linked to beef consumption).

Discovering Kuru

Drawn to epidemiological mysteries across the world, the American physician Carleton Gajdusek came to Papua New Guinea in 1957 to investigate Kuru, a peculiar disease that caused the brain to progressively deteriorate over a 6-12 month period 35 . The effects of the disease had been devastating, decimating whole villages in the remote
mountainous terrain where the Fore people lived 35 . The name Kuru means “trembling in fear” in the Fore language, describing the loss of motor function from the disease, but also perhaps the dread with which it was associated 29 . Peculiarly, the disease did not progress like other infections. The members of the tribe who developed the illness showed no fever or other signs of inflammation such as swelling, pain, and redness of the skin 29 .

Given that the disease seemed to afflict family members, scientists originally thought it was genetic 35 . However, closer analysis revealed that the disease was too prevalent and too deadly to be genetic because such a serious condition would be quickly eliminated through natural selection in such a small population as the Fore villagers 35 . Seeking another explanation in brain tissue from deceased Kuru victims, Gajdusek tried to infect small laboratory mammals with the disease but was unsuccessful 37,37 . It was only when he repeated his experiments in chimpanzees that he was able to observe the disease, as the primates developed Kuru roughly three years after inoculation with tissue from dead humans 38 .

It eventually became clear that the disease was transmitted through the Fore practice of mortuary cannibalism 35 . Following the death of a community member, the individual’s family would dismember them, preparing food from their flesh and internal organs. This practice was reflected in the epidemiology of the disease. Kuru had the highest prevalence among women, children, and the elderly because these individuals were the primary participants in cannibalism and therefore most likely to eat prion infected “morsels” such as brain tissue 35 .

In order to curb the epidemic, cannibalism was banned in New Guinea after 1959 39 . However, due to the long incubation period of Kuru, there continued to be cases among the elderly into the 1960s probably because they contracted the disease much earlier in life. For his discoveries, Gajdusek was awarded the Nobel Prize in Medicine in 1976 36 . At the time, he hypothesized that the disease was due to a “slow virus” – a virus characterized by an abnormally long incubation period 38 . While this theory now seems unlikely (at least according to the prion hypothesis), Gajdusek’s work on Kuru did stimulate work on other Kuru-like diseases, including scrapie and CJD.

Stanley Prusiner Describes Prions

Stanley Prusiner, professor of neurology and biochemistry and biophysics at UCSF.

From his first encounter with a patient afflicted with CJD in 1972, Stanley Prusiner was hooked on the problem of “slow virus” infections – the term used to describe CJD, Kuru, and scrapie at the time 40 . Working at the University of California at San Francisco, Prusiner voraciously pursued the available literature on CJD and its related illnesses and collaborated with other scientists to try to purify the agent responsible for these peculiar diseases 40 . Their efforts met with failure, and Prusiner lost his experimental funding from the Howard Hughes Medical Institute due to the seeming hopelessness of his work 40 . However, after finding support from other sources and continuing his research, it occurred to Prusiner that his inability to purify a virus responsible for scrapie might be because there was no virus to be found 40 . Perhaps he had uncovered an entirely new form of infection! He published a controversial paper in 1982 in which he coined the term “prion,” and controversy followed. Nevertheless, time and the continuing inability of other scientists to purify nucleic acids responsible for scrapie, along with further evidence in support of the “prion hypothesis,” led to gradual acceptance of Pruisner’s ideas and acknowledgement of their importance. For his contributions to the field, Pruisner was awarded the Nobel prize in Medicine and Physiology in 1997 36 .

Mad Cow Outbreak

Beginning in 1986, Mad Cow Disease, formally known as BSE, has become a major health concern in the UK and the world at large. The outbreak of a neurodegenerative disorder among British cattle in 1986 prompted veterinary researchers to investigate the matter: what they discovered were similarities between the disease killing Britain’s cow’s and human prion illnesses such as CJD and Kuru 41 .

Incidentally, the disease was being spread through the cow’s feed which contained prion-infected brain tissue from other members of the herd. In response to this discovery, UK officials placed regulations on feed content. However, it appeared the regulations had been applied to laxly, and in 1996, inadequate precautions in British slaughterhouses were linked to a variant of CJD that had appeared in patients much younger than was typical for the disease 42 . Later, epidemiological studies suggested that the disease had originated from an antelope imported from South Africa to a British safari park in the 1970s 42 . Scientists believe that the infected antelope was ground into cattle feed, transmitting the prions responsible for vCJD to herds of cows and ultimately to humans. The disease led to a ban by the European Union (EU) of beef import from Britain that lasted for 10 years. That same year, the British government began destroying herds most at risk for BSE infection. Though the public was terrified by the spread of vCJD (which had now killed 165 people in Britain), the danger of infection turned out to be lower than first thought 43 . Only individuals with a particular mutation in the PrP gene, present in about 40% of the population, can develop the disease 44 .

Though it was originally hoped to be limited to British cattle supplies, BSE began cropping up in herds worldwide. It was first identified in France in 2000, followed soon by Germany and the remaining countries in the EU 45 . Infected cows were later discovered in the US and Canada, leading experts to criticize government officials for not looking hard enough for the illness 46 . In response, both the US and Canada have begun massive quarantines and testing programs 46 . On the scientific front, researchers have begun genetic studies to engineer BSE resistant cattle. A promising recent find shows that prion resistant goat fetuses can be created by deleting the PrP gene 47 .

8 Answers 8

Besides the evident histological similarities, there are some striking parallels between the modes of transmission and symptomology of TSEs and those of Romero-Fulci disease. Here perhaps the most compelling example is kuru, an endogenous disorder unique to the Fore-speaking peoples of the eastern highlands of Papua New Guinea. Kuru, which means “trembling with fear” in the Fore tongue, reached epidemic proportions in Papua New Guinea prior to 1971, when the practice of ritual funerary endocannibalism responsible for its transmission was abolished by law. Traditionally among the Fore people the cooking and consumption of the corpse—particularly the brain—of a recently-deceased loved one was considered a gesture of respect for the departed and an integral part of the mourning process. Because kuru’s incubation period can be as long as three decades, some older Fore who participated in cannibalistic rites are still dying of the disease. However, no young person has exhibited symptoms of kuru since the practice of endocannibalism was discontinued (14). Although the incubation period of RFD is radically shorter, the similarities between it and kuru are difficult to ignore: Both are fatal neurodegenerative diseases transmitted orally by an act of cannibalism focused particularly upon the brain matter. Kuru is known to be caused by prions it therefore seems not unreasonable to propose—especially in light of the striking histological similarities exhibited in Figure 1 and Figure 2—that the causal agent in RFD is also a prion, albeit of a hitherto unknown fast-acting variety.

The main problem is that the speed of infection (or activation?) Is orders of magnitude more rapid than would be expected. The article speculates

The prion hypothesis is a strong contender, either as an alternative first cause or as a cofactor.

There may be a complex mixture of agents involved including other biological agents, poisons, and ionizing radiation. Prions are involved and behind the zombie effect, but not the sole cause. Even if prion conversion is the actual mechanism for the zombie state, other mechanisms are needed to disperse them through the tissue and catalize the needed changes.

Here’s my remix: Nanites are invented to fix tissue. They are to the point of mostly working. But unexpected prion foldings act like a bug in the system, just as they do naturally: the nanites try to “fix” things using the misfold as the exemplar! Meanwhile the body is kept working by any means the nanites can manage without caring that the brain is messed up. Rather than a persistent vegitative state though the misfolding affects the nanites themselves, making them (further) malfunction and create a Romero-style zombie.

What are the Similarities Between Virus and Prion?

  • Virus and prion are non-living particles.
  • Furthermore, they are acellular.
  • Virus and prion are harmful.
  • Both cause many diseases to be human and other organisms.
  • Also, they need a host organism to multiply.
  • Hence, they are obligate parasites.
  • Moreover, both do not contain ribosomes.
  • But, both contain proteins.
  • Furthermore, they are very small, even smaller than the bacteria.

Pathogenesis of prion diseases

The unique feature of prion diseases is that they are self-propagating and transmissible. Once PrP Sc is generated endogenously or introduced into the body from the environment, it converts normal prions into abnormal ones. This conversion begins with the initial production of a small polymer of misfolded prions, (a seed), perhaps no more than 28 molecules. This seed converts normal adjacent prions into abnormal ones by an unknown mechanism. As more PrP Sc polymers are produced, they, in turn, act as seeds, propagating the conversion of normal to abnormal prions. This novel mechanism of disease is also implicated in the propagation of protein misfolding that is involved in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

The majority of human prion diseases (see table below) are sporadic. About 15% are familial, autosomal dominant. A few are environmentally acquired (iatrogenic and from eating BSE- contaminated meat). In familial prion diseases, the change in PrP C conformation is caused by mutations of the PRNP gene (more than 40 reported), which alter its amino acid sequence. When extrinsic abnormal prions are introduced into the body, they interact with normal indigenous prions and cause them to change their conformation into abnormal. How sporadic prion disease arises, is a mystery. Perhaps the initial seed of PrP Sc is caused by somatic mutations or by posttranslational modifications.

The transmissibility of prion diseases has been proven by animal experiments. Natural transmission from animal to animal (especially in sheep) has been known for many years. In a few instances also, prion diseases have been accidentally transmitted from human to human by transplantation of tissues (dural grafts, cornea) or injection of pituitary extracts from patients with prion diseases. In 1996, transmission of bovine spongiform encephalopathy to humans was reported in the UK.

The human prion diseases are:

Creutzfeldt-Jakob disease. Sporadic-sCJD, familial-fCJD, iatrogenic-iCJD, and variant-vCJD)(see below).

Kuru. A now-extinct disease of New Guinea natives, transmitted by eating
the brains of dead persons who had the disease. Kuru is significant historically as it was the first prion disease to be discovered, and its study established the transmissibility of prion diseases.

Gerstmann-Straüssler-Scheinker syndrome (GSS). An autosomal dominant slowly progressive ataxia and dementia, characterized by widespread PrP TSE amyloid plaques throughout the CNS.

Fatal familial insomnia (FFI). An autosomal dominant sleep disorder with pathological
lesions in the thalamus.

The most common animal prion diseases are:

Scrapie. An important disease of sheep that has been known for over 100 years. Sick animals rub against rocks or other hard surfaces, scraping their fleeces. The discovery of transmissibility and other important aspects of the biology of prion diseases was based on knowledge of scrapie.

Bovine spongiform encephalopathy (BSE)-mad cow disease.

Transmissible mink encephalopathy.

Wasting disease of deer and elk.

Prion diseases have also been reported in several other domesticated and wild animal species and can cross from one species to another. Experimental transmission to primates and guinea pigs has played an important role in elucidating their pathogenesis.

Could mRNA vaccine cause prion disease?

I was wondering about possible side-effects of mRNA and I could not find answer to this question. Most of the side-effects were just about how hard is to store mRNA vaccine (temperature mostly).

I am not a prion specialist at all and even though my bachelor thesis will revolve around spliceosomes.. I am still a newbie here.

My question just come from the point, that my naive knowledge only knows, that prions are misfolded proteins, which cause other proteins to misfold and clump up. While mRNA is quite unstable. I wonder, if there is a chance of mRNA breaking down to a point, from where it would be translated into misfolded protein.

Is it easily computable, which RNA sequences will not turn into prion at all or will there always be such a chance?

Thanks, I have seen, that it may be stemming from some specific protein, but I didn't know, that it is the 'only way' to get a misfolded protein..

Think about how much rna exists in a cell and is being constantly transcribed/degraded 24/7

Pathogenic prions aren’t just misfolded proteins - they are a misfolded protein that can make other, correctly folded prion proteins take on the misfolded conformation. It’s in this way that they act like an infectious agent, and it it very, very rare for this to be possible (of human genes, I think only PRNP can do this).

Because this is not a generalisable property of misfolded proteins, and in fact is staggeringly rare, it’s very unlikely that this would happen with the vaccine.

Prions are very specific mis-folded proteins, which have the ability to cause other copies of the same protein to become mis-folded in the same way. Any old mis-folded protein will not become a prion. The body is chock full of mis-folded proteins - they are removed by your cells and dealt with all the time. Prions are really rare, super weird proteins, and again very specific. Like if a pair of scissors were broken in juuuust the right way to become a tool for turning other scissors into the same kind of broken scissors. Super unlikely and weird.

The next thing to understand is that the degradation of mRNA has nothing to do with the mis-folding of proteins. The cells translation machinery reads the mRNA to determine the order of amino acids to make a protein. If the chain of amino acids folds correctly or not after that has nothing to do with the RNA. The only way a degraded mRNA could change the protein is if the sequence of the mRNA were changed, which doesn't happen during degradation. If we think of the mRNA as like a recipe for a protein written on a piece of paper, degrading the mRNA is like burning the paper, not like scrambling the list of ingredients to produce a new recipe. So just like if I gave you a recipe for apple pie, and you lit it on fire, you wouldn't expect it to turn into a recipe for fried rice - it would just burn up. That's the concern with degrading RNA in vaccines - not that it will turn into something different, but instead that it will just break down into nothing.

To connect these two points, there is no risk that an RNA vaccine would result in prions. This would require two extremely unlikely events to happen: one for the RNA to change into a coding sequence for a different protein, instead of simply being broken down and disappearing. And two, for the sequence that the RNA changed into to be the precise coding sequence of a prion, which is a super rare and weird protein.

To push the cooking metaphor further, this would be like a recipe for apple pie catching on fire, and then instead of burning up, turning into a recipe for an intercontinental ballistic missile. It just wouldn't happen.

RNA vaccine degradation is harmless, it would just make the vaccine not work.

Immune System Oxidant Could be Key to Inactivating Prions

A product that mimics the natural oxidative killing action of human immune cells against bacteria, viruses, and fungi also can inactivate prions and other proteins, some of which are thought to be important in Parkinson’s and Alzheimer’s diseases, according to National Institutes of Health (NIH) researchers. Prions are deadly protein-based pathogens that are extremely difficult to inactivate recommended decontamination treatments often are dangerous to people or damaging to surfaces, such as those on surgical devices. There are reported cases of a prion disease (Creutzfeldt-Jakob disease, or CJD) being transmitted to patients via contaminated surgical equipment.

Scientists at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) first evaluated the product BrioHOCl in laboratory experiments using a prion diagnostic test they developed (RT-QuIC). They then confirmed the results in mice. The scientists determined that BrioHOCl eliminated all detectable prion-seeding activity for CJD, bovine spongiform encephalopathy (BSE, or mad cow disease), chronic wasting disease (a disease primarily found in deer, elk, and moose) and scrapie (a disease of sheep) in brain tissue. They conducted a portion of the study using stainless steel wire as a surrogate for surgical instruments. BrioHOCl had similar effects on two proteins thought to contribute to Parkinson’s disease and Alzheimer’s disease.

The Seattle-area company Briotech, Inc., developed BrioHOCl to remove biofilms – clusters of bacteria – from tubing and other surgical equipment. BrioHOCl is a highly purified formulation of hypochlorous acid, which immune cells produce naturally to kill microbes.

The NIAID researchers now are interested in discovering how hypochlorous acid inactivates prions, and determining whether they can harness that process to treat or prevent prion and other protein-based diseases. They also plan to evaluate whether BrioHOCl can inactivate prions associated with other tissues, fluids, tools, instruments, and environmental surfaces that may be of concern in medicine, biotechnology, agriculture, food production, and wildlife biology.

A Hughson et al. Inactivation of prions and amyloid seeds with hypochlorous acid. PLOS Pathogens DOI: 10.1371/ppat (2016).

Prions Link Cholesterol To Neurodegeneration

Prion infection of neurons increases the free cholesterol content in cell membranes. A new study 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.

It is widely believed that prions (protein only infectious material) are the cause of rare progressive neurodegenerative disorders that affect both humans and animals. A prion is an infectious agent made solely of protein. However what is not known is how the prions damage brain cells (neurons).

Dr Clive Bate and colleagues from the Royal Veterinary College in the UK compared the amounts of protein and cholesterol in prion-infected neuronal cell lines and primary cortical neurons with uninfected controls. Protein levels were similar but the amount of total cholesterol (a mixture of free and esterified cholesterol) was significantly higher in the infected cell lines.

The cholesterol balance was also affected: the amount of free cholesterol increased but that of cholesterol esters reduced, suggesting that prion infection affects cholesterol regulation. The team attempted to reproduce the effects of prions on cholesterol levels, by stimulating cholesterol biosynthesis or by adding exogenous cholesterol. Both approaches resulted in increased amounts of cholesterol esters but not of free cholesterol.

The free cholesterol is thought to affect the function of the cell membranes and to lead to abnormal activation of phospholipase A2, an enzyme implicated in the depletion of neurons in prion and Alzheimer's disease.

Studies have recently shown that the controlling cholesterol levels within the brain is critical in limiting the development of neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases, multiple sclerosis, and senile dementia. This study now gives far more specific insight into the kind of mechanisms at work. Dr Bate stated: "Our observations raise the possibility that disturbances in membrane cholesterol induced by prions are major triggering events in the neuropathogenesis of prion diseases".

Journal reference: Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2 activation. Clive Bate, Mourad Tayebi and Alun Williams. BMC Biology (in press).

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Finding out what makes a prion protein go bad may help control these brain-eating pathogens.

Prions are believed to be the cause of an array of rare but horrifying neurological diseases, such as Variant Creutzfeldt-Jakob disease (known, in cattle, as mad cow disease).

These misfolded proteins essentially eat microscopic moth holes into the brain. They are untreatable and always fatal.

Researchers at Imperial College London and the University of Zurich have now identified a critical step in the misfolding that creates a prion.

They were also able to halt the process, in a Petri dish, using antibodies — paving the way to possible treatments.

"Prion diseases are aggressive and devastating, and currently there is no cure," Imperial's Alfonso De Simone, the study's lead researcher, said in a release.

"Discovering the mechanism by which prions become pathogenic is a crucial step in one day tackling these diseases, as it allows us to search for new drugs. Now we know what we're targeting, we know what features drugs need to have to stop prions becoming pathogenic."

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A Nasty Twist: Proteins are the essential unit of life — complex molecules folded up with more turns, curls, and hairpins than a Hot Wheels track. Those folds determine the proteins' jobs and functions, which are . well, everything. Proteins are the physical stuff that makes up tissues, cells, signaling chemicals, enzymes, you name it.

Prions are proteins gone rogue, twisted like a comic book villain into pathogenic shapes. Even worse, a prion can twist other proteins it meets into its misshapen image.

As single proteins, prions are unimaginably tiny — tinier than cells, bacteria, and even viruses — but they are capable of causing devastating diseases. Usually, prion diseases occur spontaneously or from inherited genetic mutations, but rarely, they can be transmitted through contaminated food, blood, or surgical instruments.

These are called transmissible spongiform encephalopathies, the most famous of which is bovine spongiform encephalopathy — aka mad cow.

That "spongiform" part is a funny word for a very unfunny condition. The prions cause a cascade of misfolding that basically turns your brain into a sponge, riddled with tiny holes.

Luckily, human prion diseases are quite rare Johns Hopkins pegs the number of cases at around 300 a year in the U.S. These diseases include kuru — originally identified among populations that practiced ritual cannibalism, and now all but eliminated — and the most common form in humans, Creutzfeldt-Jakob disease (CJD).

Human prion protein naturally occurs in the body, but it is "usually well behaved," says Valerie Sim, an associate professor at the University of Alberta's Centre for Prions and Protein Folding Disease, who is not affiliated with the Imperial College/Zurich study.

Human brain tissue from a patient with variant Creutzfeldt-Jakob disease showing the spongification of brain tissue and loss of neurons that are the hallmarks of prion disease. Credit: Sherif Zaki MD, PhD Wun-Ju Shieh MD, PhD, MPH / CDC

But sometimes (hence the name), prion protein will twist the wrong way, triggering a domino effect that ends in disease and death.

It's that moment, when the prion breaks bad, that the researchers were looking to figure out.

Into the Fold: For their study, published in PNAS, the researchers compared normal human prion protein with a mutated, pathogenic version.

The mutant prion protein was chosen for its aggressive, contagious nature — more prions equals more opportunities to try and catch them in the act. To do so, the researchers used advanced imaging techniques backed up with computer analysis.

The researchers found a specific spot on the prion where it began to fold into the pathogenic form. The University of Zurich team then produced antibodies that took aim at that exact spot. When the mutant prions were exposed to the antibodies in a test tube, they did not fold into their pathogenic shape.

"That supported their hypothesis that this spot on the mutant protein is the driver of misfolding," Sim says.

The antibody's success also serves as a proof-of-concept, of sorts, for potential prion therapies that take aim at folding sites.

"Now (researchers) are saying 'we think it's this specific spot on the prion protein that's the trouble spot,'" Sim says. If a molecule could be found that blocks or stabilizes that spot, it could finally provide a prion treatment.

"How you do that is a whole other level of investigation," Sim says.

Besides being performed in vitro, the study comes with a few other caveats. While the site the researchers identified may be the starting point for the mutated prion protein's bad fold, it's not necessarily the same place it happens in the regular human prion protein without the same mutation.

As single proteins, prions are unimaginably tiny — tinier than cells, bacteria, and even viruses — but they are capable of causing devastating diseases.

Also, while the team's mutated prion protein is known to cause disease in humans, the researchers did not infect an animal model with their proteins, so they didn't prove the ability of these specific prions to cause disease. Unlike a virus, this can't be determined just by looking at it: it's actually pretty tricky business growing a pathogenic prion, Sim says — usually, you need to use slurried infected brain matter.

Still, the finding may prove an important insight into the unusual pathogens.

"The intermediate stage of prion pathogenesis is so transient it's like a ghost — almost impossible to image," study lead author Máximo Sanz-Hernández says in the release.

"But now we have a picture of what we're dealing with, we can design more specific interventions that can one day potentially control these devastating diseases."

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Researchers Identify What Causes Prions to Become Pathogenic

Prion diseases occur when normal prion protein, found on the surface of many cells, becomes abnormal and clumps in the brain, causing brain damage. Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare progressive neurodegenerative disorders that affect both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response. Unfortunately, prion diseases are usually rapidly progressive and always fatal. Human prion disease include Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia, and Kuru.

Now, researchers from Imperial College London and the University of Zurich report they have determined what causes normal proteins to convert to a disease form. They also report they have found a way to block the process, which may lead to new therapeutics.

Their findings are published in the Proceedings of the National Academy of Sciences (PNAS) in a paper titled, “Mechanism of misfolding of the human prion protein revealed by a pathological mutation.”

“Discovering the mechanism by which prions become pathogenic is a crucial step in one day tackling these diseases, as it allows us to search for new drugs,” explained lead researcher and professor Alfonso De Simone, from the department of life sciences at Imperial College London. “Now we know what we’re targeting, we know what features drugs need to have to stop prions becoming pathogenic.”

Prion protein (PrP) misfolding is a key part of the disease process. Proteins fold into 3D shapes that cause disease. The researchers used a mutant form of the prion protein that is found in people with inherited prion diseases as a model for observation.

Using nuclear resonance spectroscopy combined with computational analysis, the researchers were able to locate the structure of the intermediate step to reveal the molecular mechanism behind prion misfolding.

The structure of normal and mutant PrP proteins. [Imperial College London] The researchers from the University of Zurich were able to produce antibodies that could target the mechanism. Currently, the antibodies are too large to pass into the brain, but the findings show promise for blocking the mechanism and will lead to the development of new therapeutics.

“The intermediate stage of prion pathogenesis is so transient it’s like a ghost—almost impossible to image. But now we have a picture of what we’re dealing with, we can design more specific interventions that can one day potentially control these devastating diseases.”

The researchers hope their discovery will help drug researchers and pharma companies pinpoint drug compounds that can block the mechanism and pass through the brain.