Prions

By pjain      Published July 26, 2021, 6:57 p.m. in blog Health   

Prion Biochemistry

What

Prions are misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein.

Prions Are forms of amyloids - accumulate

Prions form abnormal aggregates of proteins called amyloids, which accumulate in infected tissue and are associated with tissue damage and cell death.

Amyloids are also responsible for several other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Biochemical Properties

Ultra Structural Stability

Prion aggregates are stable, and this structural stability means that prions are resistant to denaturation by chemical and physical agents: they cannot be destroyed by ordinary disinfection or cooking. This makes disposal and containment of these particles difficult.

Prions appear to remain infectious even after being exposed to treatments that destroy nucleic acids eg from viruses, etc - making sterilization of medical instruments problematic.

Misfolding of Normal Proteins and Causes

It is not known what causes the normal protein to misfold, but the abnormal three-dimensional structure is suspected of conferring infectious properties, collapsing nearby protein molecules into the same shape. The word prion derives from "proteinaceous infectious particle".

Several yeast proteins have also been identified as having prionogenic properties. Prion replication is subject to epimutation and natural selection just as for other forms of replication, and their structure varies slightly between species.

PrP normal state pN converts to a Prion pD state that causes disease

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.

Pathogenic or Virino Hypothesis of Transmission and Amplification

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.

Some researchers believe that the prions are formed when PrP associates with a foreign pathogenic nucleic acid. 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 means that prions transmit and reproduce without pathogens as causes.

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.

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.

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.

So after injection into victims, exponential amplification of the prion (converting pN into pD in the body) would then result in disease that is extensive enough in the victim to be a problem.

Impact, Diseases, Detection, Treatment

Prion Diseases 101

In people with prion disease, misfolded PrP can bind to healthy PrP, which causes the healthy protein to also fold abnormally.

Misfolded PrP begins to accumulate and form clumps within the brain, damaging and killing nerve cells.

This damage causes tiny holes to form in brain tissue, making it appear sponge-like under a microscope. In fact, you may also see prion diseases referred to as “spongiform encephalopathies.”

Prions characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. Prion isoforms of the prion protein (PrP), whose specific function is uncertain. A prion disease is a type of proteopathy, or disease of structurally abnormal proteins.

Prion diseases cause a progressive decline in brain function due to misfolding of proteins in the brain — particularly the misfolding of proteins called prion proteins (PrP) whose normal function and role is unknown.

This hypothesized role of a protein as an infectious agent stands in contrast to all other known infectious agents such as viroids, viruses, bacteria, fungi, and parasites, all of which contain nucleic acids (DNA, RNA, or both).

All known prion diseases in mammals affect the structure of the brain or other neural tissue; all are progressive, have no known effective treatment, and are always fatal.

Collectively these diseases are known as transmissible spongiform encephalopathies.

Symptoms

Prion Diseases can cause changes in: memory behavior movement

Prion diseases have very long incubation periods, often on the order of many years. When symptoms develop, they progressively worsen, sometimes rapidly. Common symptoms of prion disease include:

difficulties with thinking, memory, and judgment
personality changes such as apathy, agitation, and depression
confusion or disorientation
involuntary muscle spasms (myoclonus)
loss of coordination (ataxia)
trouble sleeping (insomnia)
difficult or slurred speech
impaired vision or blindness

Diagnosis

Since prion diseases can present similar symptoms to other neurodegenerative disorders, they can be difficult to diagnose.

The only way to confirm a diagnosis of prion disease is through a brain biopsy performed after death.

However, a healthcare provider can use your symptoms, medical history, and several tests to help diagnose prion disease.

Magnetic resonance imaging (MRI). An MRI can create a detailed image of your brain. This can help healthcare providers visualize changes in brain structure that are associated with prion disease.

Cerebrospinal fluid (CSF) testing. CSF can be collected and tested for markers associated with neurodegeneration.

In 2015, a test was developed to specifically detect markers of human prion disease.

Electroencephalography (EEG). This test records electrical activity in your brain.

Transmission

The normal function of these proteins is currently unknown.

Acquired - Insertion into Victims

Prions can be transmitted, possibly by eating and certainly by inoculation either directly into the brain or into skin and muscle tissue e.g. by contaminated medical equipment.

Mutations - pN to pD flipping

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.

Inheritance of Mutation from Ancestors

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 and inheritance would increase the probability of pN transforming into pD, so that the disease would almost certainly occur.

How pD forms are Neuro-Degenerative

Scientists as of 2020 did 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 like the class of amyloids.

One part of the prion protein can cause apoptosis, or programmed cell death; perhaps this mechanism explains the pattern of the disease.

--- Animal Diseases

Prions are hypothesized as the cause of following diseases

Transmissible spongiform encephalopathies (TSEs) and scrapie in sheep

Chronic wasting disease (CWD) in deer

BSE or Mad Cow Disease prevalent in UK

--- Human Diseases and Prions Overview

Kuru - 1950s

In the 1950s an epidemic transmissible disease called kuru, similar to CJD, was identified in the Fore tribe of Papua New Guinea. Transmission of the disease occurred during a ritual funeral process in which the brain of a dead tribe member was removed from the skull, cooked and eaten.

Scientific analysis of the brains of people who had died from CJD or kuru showed that their brain tissue had a spongiform appearance, that is, there were holes where cells ought to be, indicating an encephalopathy, or reduction in the number of brain cells.

D. Carleton Gajdusek, NIH demonstrated that extracts of brain prepared from people who had died of CJD or kuru could cause a similar disease when inoculated into the brain of chimpanzees. These experiments obviously suggested the presence of an infectious agent. That inference has been confirmed by the inadvertent transmission of CJD to patients undergoing various medical treatments, such as corneal transplants and human growth hormone therapy.

Creutzfeldt–Jakob disease (CJD) 1920

First described in 1920, CJD can be acquired, inherited, or sporadic. Most casesTrusted Source of CJD are sporadic i.e. formed by mutations.

"The cause of CJD was unknown for many years; it occurred seemingly randomly, at a very low incidence. In the 1950s an epidemic transmissible disease called kuru, similar to CJD, was identified in the Fore tribe of Papua New Guinea. Transmission of the disease occurred during a ritual funeral process in which the brain of a dead tribe member was removed from the skull, cooked and eaten. Scientific analysis of the brains of people who had died from CJD or kuru showed that their brain tissue had a spongiform appearance, that is, there were holes where cells ought to be, indicating an encephalopathy, or reduction in the number of brain cells." - Shaun Heaphy, Leicester Univ

CJD Variant - vCJD

his form of CJD can be acquired through eating the contaminated meat of a cow.

Gerstmann–Sträussler–Scheinker syndrome (GSS) - Inherited

GSS is also inherited and it’s transmitted in a dominant manner. It affects the cerebellum, which is the part of the brain that manages balance, coordination, and equilibrium.

Researchers 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.

Fatal familial insomnia (FFI)

FFI affects the thalamus, which is the part of your brain that manages sleeping and waking cycles. One of the main symptoms of this condition is worsening insomnia. The mutation is inherited in a dominant manner, meaning an affected person has a 50 percent chance of transmitting it to their children.

Role in AD, Parkinsons, ALS

There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS); these have been termed prion-like diseases.

--- Transmission

Any explanation for the cause of a prion disease therefore has to account for random, inherited and transmitted variants of the disease.

Incidence - Rare

Prion diseases are very rare. Approximately 350 new cases of prion disease are reported each year in the United States.

Treatments - None, mainly Palliative

There are no effective treatments for prion diseases and while rare they are inevitably fatal.

Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.

Although some potential treatments have shown promise in the laboratory, none has been effective once the disease has commenced.

Medications. Some medications can be prescribed to help treat symptoms. Examples include: – reducing psychological symptoms with antidepressants or sedatives – providing pain relief using opiate medication – easing muscle spasms with drugs like sodium valproate and clonazepam

Assistance. As the disease advances, many people need help taking care of themselves and performing daily activities.

Providing hydration and nutrients. In advanced stages of the disease, IV fluids or a feeding tube may be required.

Pharma Advanced Developments

Some of the potential therapies that are being investigated include use of anti-prion antibodies and “anti-prionsTrusted Source” that inhibit replication of abnormal PrP.

Research Overview

Timeline

1950s, Carleton Gajdusek eventually showed that kuru could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 Nobel prize.

Investigations by E.J. Field into scrapie and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.

1960s, Radiation biologist Tikvah Alper and biophysicist John Stanley Griffith, developed the hypothesis that the transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins. They wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt–Jakob disease resisted ionizing radiation. Griffith proposed three hypothesis for ways in which a protein could be a pathogen.

I1. If the protein is the product of a normally suppressed gene, and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then go wake the gene up in other cells.

  1. This also forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.

  2. The agent could be an antibody if the antibody was its own target antigen, as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this hypothesis was unlikely to be true due to the lack of a detectable immune response.

1970 Francis Crick recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith). The revised hypothesis was later formulated, in part, to accommodate reverse transcription (which both Howard Temin and David Baltimore discovered in 1970).

1982, Stanley B. Prusiner of the University of California, San Francisco, announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement. The protein was named a prion, for "proteinacious infectious particle", derived from the words protein and infection. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.

Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory. Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.

Until 2015, all known mammalian prion diseases were considered to be caused by the prion protein (PrP);

2015 multiple system atrophy (MSA) was hypothesized to be caused by a prion form of alpha-synuclein.

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Fundamentals 101

  • "Madness and Memory: The Discovery of Prions -- A New Biological Principle of Disease" by Stanley B. Prusiner (1997 Nobel laureate), Yale University Press, 2014. hv
  • Prions_ the new biology of proteins 2006 hv

hCare and Policy

Rare so little Impact

Weaponization

Prions can be employed as a weaponized agent. With potential fatality rates of 100%, it makes prions a very effective bio-weapon choice. However, one unfavorable aspect is that prions have very long incubation periods. On the other hand, persistent and heavy exposure of prions to intestine, might shorten the overall onset. Also, one large benefit for using prions in warfare, is that detecting prions and decontaminating them is rather difficult.

Prevention

Several measures have been taken to prevent the transmission of acquired prion diseases. Because of these proactive steps, acquiring a prion disease from food or from a medical setting is now extremely rare.

Some of the preventive steps taken include:

  • Setting tight regulations on importing cattle from countries where BSE occurs

  • Prohibiting the parts of the cow such as the brain and spinal cord from being used in food for humans or animals

  • Preventing those with a history of or risk for exposure to prion disease from donating blood or other tissues

  • Using robust sterilization measures on medical instrument that has come into contact with the nervous tissue of someone with suspected prion disease

  • Destroying disposable medical instruments

Genetic Identification and Awareness

There’s currently no way to prevent inherited or sporadic forms of prion disease.

If someone in your family has had an inherited prion disease, you may consider consulting with a genetic counselor to discuss your risk of developing the disease.

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  • OECD - Emerging diseases _ prions and viruses 2009 hv
  • Prions_ A Challenge for Science, Medicine and Public Health System 2001 hv

Food Systems Role and Policy

BSE or Mad Cow Disease prevalent in UK

  • Bovine spongiform encephalopathy (BSE) in cattle (commonly known as "mad cow disease") BSE is more dramatically known as mad cow disease but the normal incidence of BSE is vanishingly small, however.

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 U.S. Department of Agriculture claims that BSE has not been identified in any U.S. cattle.


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