Prion

Four nerve cells in a mouse; the red parts show prion proteins, which are transmitted along neurites (projections between cells).

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Prions are misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein. Prions are the cause of many fatal diseases. While most prion diseases are neurological, some can affect other parts of the body. Prions are most known for their role in transmissible spongiform encephalopathies (TSEs), but they are the cause of other diseases including multiple system atrophy, Alzheimer's disease, Huntington's disease, and some forms of amyloidosis.

Pathology of prions

Proteins, when exposed to enzymes that break them down (proteases), are chopped up into small bits (technically, the protein is protease-sensitive). However, when the normal prion protein (PrP^C) folding occurs, the proteins may misfold into the pathogenic/infectious form (PrP^Sc), after which it then causes disease. This has three effects:

1. The protein is highly protease-resistant
2. The protein has the ability to cause other variants of the same protein to adopt their form
3. The prions become the most potent known neurotoxin

Once a misfolded prion protein (PrP^Sc) comes into contact with normal protein prion protein (PrP^C) it converts the PrP^C into PrP^Sc (a domino effect). Prion infections are currently untreatable, although some people seem to have evolved a degree of resistance (most notably the Fore people due to consistent encounters with kuru over several generations, some of whom went 45 years after initial contact before becoming symptomatic). While prions do not appear to be capable of airborne transmission naturally, a study showed that an artificial prion aerosol can cause certain death to mice within a minute of exposure. This opens the doors to a potential prion terrorist attack; however, there is very little to fear, as the 30-year incubation time would make the spike in cases hard to link to the attack as well as an unappealing method for a terrorist.

Prions are extremely resistant to all forms of destruction. They can survive incineration, ionizing radiation, autoclaving, and they can persist in soil for hundreds of years, remaining infectious. Prions are similar to radioactive fallout, if fallout was infectious and near-undetectable. They also stick to stainless steel within seconds.

While PrP is the most famous prion, (literally: prion protein), other proteins can become prions in a similar way. Multiple system atrophy is caused by prion isoforms of α-synuclein. Alzheimer's disease is also a prion disease, but it's especially notable not just because 450,000-700,000 fall victim to this disease every year, but because evidence shows that the prions involved can misfold other types of proteins. The prions that cause Alzheimer's are beta-amyloid and tau.

Transmission

There are three types of prion disease — infectious, sporadic, and genetic.

1. In the infectious form, one gets the disease by contact with infected materials or tissues. The nervous system tissue is the most infectious material. Prion disease can spread by blood, and prion-laced blood transfusions have been linked to at least 4 deaths. Infectious also covers iatrogenic transmission (getting the disease from infected medical instruments — don't think too hard about where that endoscope went last!).
2. The sporadic form occurs when proteins misfold for a reason not yet known to medical science. The most common theory is that proteins misfold all the time, but the faulty proteins are broken down by proteases. However, prions are resistant to proteases, so they fail to be broken down, and spread their corrupted form. Some scientists believe a toxin could amplify this process.
3. For the genetic prion diseases, prions are caused by a mutation of the PRNP human protein gene. Genetic prion diseases are the rarest out of the three of them. The most notable genetic prion disease is fatal familial insomnia, a genetic disorder present in only 30 families worldwide.

Transmissible spongiform encephalopathies

Contagious sponge-brain disease Transmissible spongiform encephalopathies are neurodegenerative brain diseases exclusively caused by prion isoforms of the prion protein (confusing, right?) called PrP^Sc or PrP^res. They are also protease resistant, and extremely neurotoxic. They affect humans and animals alike, and have been shown to cross the species barrier easily. They have extremely long incubation periods; in humans they can be up to 50 years. The name 'spongiform encephalopathy' comes from the fact that they literally rip holes in your brain. Symptoms in humans include dementia, ataxia, depression, paralysis, and always lead to death. In the US, there are about 350 cases per year.

In humans

Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease, also known as subacute spongiform encephalopathy, is a neurodegenerative brain disease that usually occurs in people between the ages of 50 and 65. Its symptoms include ataxia, dementia, speech issues, quadriplegia, and death is certain after 18 months, while most only survive 6. The incubation period is estimated at about 30 years. It has three forms, based on the way that the person was infected.

Sporadic

Sporadic CJD is just that — CJD without a known cause. This form makes up the majority of cases. Some scientists speculate that sporadic misfoldings are natural, but the faulty proteins are usually broken down. Others think it could be a toxin, and there appears to be significant evidence to show that they can affect protein folding, but none conclusively tying it to TSEs or other prionopathies.

Iatrogenic

Iatrogenic CJD is when the exposure to prions is linked to a medical procedure. This can include tainted blood transfusions, contaminated neurosurgical tools, infected organ transplants, and other medical procedures involving blood or brain matter transmission.

An epidemic of iCJD occurred after human growth hormone taken from cadavers became contaminated with prions. 226 cases of iCJD were linked to the faulty treatment, and the exposed patients also have a higher chance of contracting Alzheimer's disease.

Familial

Familial CJD is when a gene inherited from a parent is faulty, and produces abnormal prions. All familial TSEs are autosomal dominant mutations, meaning that only one copy of the mutated PRNP gene will cause the disease, and any children that the person has will have a 50% chance of carrying the gene. It is estimated that 5-15% of all cases of CJD are familial.

Variant Creutzfeldt-Jakob disease

Variant CJD is a disease directly linked to the consumption of beef contaminated with bovine spongiform encephalopathy. Unlike CJD, it affects younger people, with the median age of onset being 28. The symptoms are almost identical to CJD, but the prion involved is thought to be exactly the same isoform as the BSE-causing prion. Affected patients survive on average for 18 months, but the disease is still always fatal. However, one infected person survived for over ten years.

An epidemic of this variant in the UK killed 177 people, several cats, and almost a million cows. The cause was infected meat and bone meal (MBM). The incineration process failed to destroy the resistant prion protein, and when cows ate the tainted food, they would become infected. Their remains were turned into MBM, causing the disease to spread rapidly.

Fatal familial insomnia

Fatal familial insomnia is a disease that is characterized by the complete inability to sleep i.e. living Hell. The first signs of the disease are progressive insomnia, which leads to the classic signs of a TSE. Eventually, the victim will not be able to sleep. Sleeping pills will just accelerate the progression of the symptoms, and as the name suggests, the disease is terminal. FFI is usually caused by a malformed gene, but very rarely, it can happen sporadically.

Gerstmann-Sträussler-Scheinker syndrome

Gerstmann-Sträussler-Scheinker syndrome is a familial TSE that occurs in people from the age of 35-50. The symptoms include progressive ataxia, dementia, slurred speech, abnormal eye movements, rigid muscles, deafness, and Parkinsonism (in some cases).

Kuru

Kuru, literally 'shaking disease' (from the Fore language), is a TSE associated with ritual mortuary cannibalism. Symptoms include the classic TSE symptoms, as well as shaking uncontrollably, and bouts of laughing (which is always quite mirthless), causing some to call it the 'laughing disease'. The Fore people had an epidemic of this disease due to them consuming the bodies of people who died.

Variably-protease sensitive prionopathy

Variably-protease sensitive prionopathy is a disease very similar to sCJD, but stands out due to all tests for CJD showing nothing in VPsPr patients. It is very hard to diagnose and commonly mistaken for CJD or Alzheimer's disease.

In animals

Bovine spongiform encephalopathy

See the main article on this topic: Bovine spongiform encephalopathy

Commonly known as mad cow disease, BSE is a prion disease affecting cows. It is extremely rare, however if infected meat and bone meal is fed to cows, it can spread very rapidly. BSE can spread to humans, and is called variant Creutzfeldt-Jakob disease. The UK had an epidemic caused by poor farming practices; meat and bone meal was fed to cows, and when the cows died from the disease, their remains were ground up into more MBM, causing the disease to spread exponentially. Almost a million cows, several cats, and 177 humans died in the epidemic. Worryingly, a new variant of BSE, called atypical BSE, has been shown to be similar to sporadic CJD, however no link has been established between the two.

Scrapie

Scrapie is a TSE affecting sheep and goats. It was the first prion disease ever, discovered in 1755 (though its relation to prions was not discovered until the 20^th century). The signs of scrapie are abnormal gait, ataxia, and compulsive scraping. Scrapie does not appear to be able to infect humans, and the disease has been eradicated in most countries. It is extremely infectious, and a pen that housed infected sheep was disinfected with strong acids, repainted, and the metal was replaced. Sheep placed in it were infected within a year.

Chronic wasting disease

Chronic wasting disease is a TSE affecting deer. The symptoms include severe weight loss, loss of fear of humans, and fur loss. It is the most infectious of all TSEs, and has an R0 of 3.2! Since the disease is 100% fatal, that means for every deer infected, approximately 3-4 deer will die. While this disease doesn't appear to affect humans, there is weak evidence linking it to clusters of CJD cases. While the CDC says that the risk is minimal, it still recommends to take safety precautions, and not to eat infected meat. Infected deer are still a danger to humans, as they have a tendency to stand in roads, which can pose a hazard for drivers.

Other spongiform encephalopathies

• Feline spongiform encephalopathy
• Ungulate spongiform encephalopathy
• Primate spongiform encephalopathy
• Ostrich spongiform encephalopathy
• Camel spongiform encephalopathy
• Transmissible mink encephalopathy

Non-TSE prion diseases

Alzheimer's disease

Alzheimer's disease is a prion disease notable for 2 reasons: It is caused by 2 different prions, amyloid-beta and tau, and there are almost 600,000 cases per year. Alzheimer's disease is the 6th leading cause of death in the US, and is the only disease in the top 10 causes of death that cannot be prevented or cured. One third of people over 85 are suffering from the disease, and every 66 seconds someone develops Alzheimer's.

The disease is universally fatal. While it's believed to be sporadic, there are many genetic factors that increase the chance you will be infected. Most people living with the disease are above the age of 60. The disease is neurodegenerative, and tends to set in much more rapidly if it begins prior to the age of 65. The flagship symptom of Alzheimer's disease is dementia. On an MRI, amyloid plaques can be seen to confirm the diagnosis.

Multiple system atrophy

Formerly known as Shy-Drager Syndrome, multiple system atrophy is a prion disease that affects the nervous system. The prion responsible is alpha-Synuclein. It is transmissible, and sporadic, meaning there is no known cause. The disease is very similar to Parkinson's disease, making diagnosis hard. The median age of onset is 55 years. There are 2 forms of MSA. Symptoms that are present in both forms include dizziness, loss of balance, a low pitched voice, fainting, urinary incontinence, and rigid muscles. The disease is universally fatal, with a survival time of 7 years.

The parkinsonian type of MSA is the most difficult to diagnose. All of the unique symptoms in MSA-P are the same as Parkinson's disease. The second type is the cerebellar form, known as MSA-C. MSA-C is similar to Creutzfeldt-Jakob disease in that its main symptom is ataxia. Difficulty swallowing, severe speech abnormalities, and abnormal eye movements are the distinguishing symptoms of MSA-C.

Huntington’s disease

Huntington's disease is a hereditary neurodegenerative prion disease of the brain. Unlike many genetic disorders it is a dominant allele, so one affected parent has at least a 50% chance of passing it on. It is characterized by a slow neurological decline, with the end result being the complete inability to move or function. Like other prion diseases, it is always fatal and incurable. The age of onset of the disease varies wildly, with onsets as early as 2 years of age, up to 85 years. Usually the disease manifests between age 30-60, though rarely it can set in during teenage years. Once symptoms appear, life expectancy is between 10 and 20 years.

The disease has 5 distinct stages, with the first stage being very mild, and the fifth being end-of-life.

Stage 1: Before diagnosis

The first stage is almost unnoticeable. Doctors are unable to diagnose the condition at this stage. Minor mood problems and thinking issues are the first symptoms.

Stage 2: Early

Affected people are usually formally diagnosed at this stage. Twitches and slight tremors are present, but they can be mistaken for stress. Simple tasks become difficult. Depression, anxiety, and anger issues become much worse. Eating becomes slightly more difficult, and insomnia and waking up during sleep occur. While the affected can usually drive to work and are able to complete tasks at work, they will need help doing some of their daily activities.

Stage 3: Moderate

Walking becomes more difficult. Most people will need a wheelchair at this stage. Thinking is severely impaired. Depression becomes crippling, and sufferers will no longer be able to drive or work. Severe difficulty in swallowing is observed. People affected will need a full time caretaker as they are no longer able to carry out daily tasks. Insomnia becomes severe.

Stage 4: Severe

By this stage, walking is impossible and the affected become bedridden. Using the bathroom is impossible. They cannot talk, and it's extremely hard to sleep. A feeding tube becomes required. They are unable to do anything for themselves, and require 24/7 care. Euthanasia is a choice, as the person is completely unable to move and is in a lot of pain.

Stage 5: End of life

In Stage 5, the person is usually in a vegetative state. Like other prion diseases, Huntington's disease does not kill directly, and it's possible for the person to live several more years in a vegetative state. The usual cause of death is pneumonia due to aspiration of food, or the family deciding to take the person off of life support.

Misinformation

Unfortunately, there is a lot of misinformation and discredited science surrounding TSEs.

Spiroplasma

While the scientific consensus is that all TSEs are caused by prions, one scientist has disputed this. Frank O. Bastian has published several papers claiming that the bacterium Spiroplasma is the true cause of TSEs, specifically CWD. The evidence seems convincing - but there are many issues with his research.

No other scientists were able to replicate his findings. In addition, a study done in 2006 directly refutes the theory. While he was able to cause CWD in deer by injecting them with Spiroplasma, he took the bacteria from the brain of deer already infected. This would almost certainly contaminate the sample with PrP^Sc. Any disinfection procedure that would destroy the prions would also kill the bacteria. The bacteria infects plants, and any deer that ate the infected plants would become a carrier. However, they are likely asymptomatic. This explains the presence of the bacteria in CWD-infected deer. Since no uninfected deer were tested, there is no way to prove that the bacteria is only present in cases of CWD.

60,000 cases

A study by Laura Manuelidis showed that 13% of Alzheimer's disease cases were actually CJD. With over 500,000 cases of Alzheimer's per year, that could be up to 60,000 missed cases of CJD, per year. While the study is real, it suffers from a low sample size. They only tested 60 patients. A later study shows that while it is true that there are misdiagnosed CJD cases, the number is far lower. Out of 6,000 cases, 19 cases were shown to be a misdiagnosed TSE. This would put the number at 1,584 more cases, if all 500,000 have the same error rate.

COVID vaccine prion "study"

See the main article on this topic: COVID-19 pandemic

In May of 2022, a "study" was released linking CJD, a prion disease, to mRNA COVID-19 vaccines. This study has not been peer-reviewed, is full of informal language, unsourced content, grammatical errors, and broken formatting. It relies on a case of CJD detected after a man was infected with COVID-19. This case is real, but it was after the COVID virus, not the vaccine.^{[citation needed]} It falsely links mRNA to prion diseases. One of the three co-authors, Luc Montagnier who had been suffering from Nobel disease, died shortly before the study was released to the public. Montagnier died at age 89 of unknown causes, but that did not stop a conspiracy theorist claiming that he was murdered for exposing the 'truth' about vaccines.

COVID-19 and TSEs

COVID-19 has been linked to TSEs, by both scientists, and cranks.

Acceleration of prion disease pathogenesis

A paper released in July 2020 showed a case of sporadic Creutzfeldt-Jakob disease in a previously healthy man in his 60s, who was infected with COVID-19 when the symptoms started. It was likely a coincidence, but it's possible that the mild brain damage caused by COVID-19 could have accelerated the disease.

SARS-CoV-2 transmission by prions

Multiple articles from reputable sources have used misleading wording to imply that SARS-CoV-2 uses prions to infect cells. However, what was actually demonstrated was 'prion-like' proteins and prion-like domains. The only reasoning for the name is the fact that the N protein can change its folding to adapt to the host's cells. The name 'prion-like' is highly misleading. Prions do not change their folding to adapt to infect proteins. Prions are instead a misfolded version of a host protein, that cause other proteins to change shape. In addition, they generally only infect the same type of proteins that they are a variant of.^{[citation needed]}

mRNA vaccines cause Prion disease

See article COVID-19 denialism for more information

In the tradition of anti-vaccine pseudoscience, there is a nonsensical claim that the COVID-19 vaccine causes Prion diseases such as vCJD. This idea is a revamp of the older idea that flu shots cause Alzheimer's Disease. The newer version of the conspiracy is that Fetal Bovine Serum used in vaccines is contaminated with prion protein. This has never been confirmed in randomized clinical trials and no evidence of prion contamination in vaccines has ever been demonstrated. This is one of many pieces of dangerous anti-vaccine pseudoscience. Others who have suggested links include Stephanie Seneff, and Kevin W. McCairn who suggested links between vaccines and amyloids along with prions.

Treatments

Real treatments

While no cure has been found for human prion diseases, there have been treatments that are able to extend the life of those affected.

Quinacrine

Quinacrine was one of the first non-quack treatments that showed promise. The drug was able to significantly slow the misfolding of PrP^c to PrP^Sc in prion-infected neuronal cells. While PrP^Sc levels diminished in mice after treatment, their survival time was not increased. Clinical trials in humans showed no effect, likely because the treatment couldn't cross the blood-brain barrier. In addition, the treatment caused severe liver and kidney damage. The drug was retired.

Antibodies

Antibodies against PrP could be a promising treatment for TSEs. It could also translate to treatments for other prion diseases, such as Alzheimer's disease and Huntington's disease. Antibody treatments are not novel; drugs such as Humira and Herceptin are injected antibodies. An antibody called PRN100 was the first developed antibody to treat TSEs. It was able to completely cure prion-infected cells in a petri dish. Mice were also cured, if treated during the early stages of the incubation period. If treated after becoming symptomatic, their survival time was tripled. 6 patients have been treated with the antibody, but it wasn't successful. All of the patients died without any noticeable improvement in symptoms.^{[citation needed]}

A more radical solution?

No PrP^c means no chance of misfolding into PrP^Sc. This was demonstrated as early as 2003 in mice. Mice that had all their PrP removed while infected with a TSE were completely cured. Unfortunately, you can't just remove all PrP in a human; the mice were genetically modified with a genetic trigger that allowed the scientists to 'shut off' the PRNP gene. It's possible to eliminate the PRNP gene completely, and doing so causes the organism to be completely immune to TSEs. While this is farfetched at best in humans, it could be done to cows to allow for a complete immunity to bovine spongiform encephalopathy. This would allow for all parts of the animal to be used without danger, causing less damage to the environment, eliminating the potential for another BSE epidemic, and allowing cow farmers to make more money by using meat and bone meal and selling more parts of the cows. It's a win-win for everyone but the GMOphobes.

Woo

As with any deadly disease, there are quacks who promote woo. Earth Clinic, which is a natural health website, claims that apple cider vinegar and caprylic acid can treat the symptoms. However, if someone ingests too much caprylic acid it may cause pain in the gastrointestinal tract. Caprylic acid is fairly safe if taken in small amounts; outside that it does nothing to help with symptoms.

See also

• Mad Cow Disease
• Medicine

External links

• CDC page on prions
• University of Utah on prions