What is Prions?
- Prion is an abnormal or misfolded protein that causes fatal disease in animals and humans by transmitting their misfolded shape onto normal variants of the same protein.
- Prion causes untreatable, fatal, and transmissible neurodegenerative diseases in both humans and animals. In this disease, a progressive decline is occurring in brain function.
- In 1982 an American neurologist and biochemist Stanley Benjamin Prusiner first coined the term Prion. The term prion derived from “proteinaceous infectious particle”.
- Their mode of infection is totally different from bacteria, viruses, and other infectious pathogens; they lack genetic material.
- Prions are made of a protein called prion protein (PrP).
- This disease is very rare, about 350 new cases reported each year in the US.
- In this disease, the PrP accumulates in brain cells and starts to form clumps and then it starts damaging and killing nerve cells.
- It damages the brain cells by forming tiny holes that appear sponge-like structure under a microscope.
- The incubation period of prion disease is about 5 to 20 years.
Characteristics of Prion Protein
- Prions are smaller than a virus and can be seen under an electron microscope.
- They only appear in electron microscopes when they have aggregated and formed a cluster.
- Prions lack nucleic acids. Hence they are resistant to those procedures which are used to destroy pathogens by breaking down nucleic acid.
- Prions do not trigger a host immune response because they are the abnormal version of a normal protein.
- The normal PrP is composed of a flexible coil known as alpha helices, whereas in abnormal PrP these helices are stretched out into densely packed structures called beta-sheets.
- PrP is resistant to proteases enzyme, heat, ionizing radiation, and formaldehyde treatments.
- In 2011 researchers found that prions can be transmitted through airborne particles such as aerosols.
- The prion can be decontaminated by protein hydrolysis or reduction or destruction of protein tertiary structure, which can be accomplished by the sodium hypochlorite, sodium hydroxide, and strongly acidic detergents such as LpH.
- Researchers currently study ozone sterilization as a potential method for prion denaturation and deactivation.
Structure of Prion Protein
The prion protein exists throughout the body of a healthy animal and people. There are present two forms of prion protein such as;
- PrPC, it is considered as the normal form of protein. Here C refers to ‘cellular’ PrP. this protein is structurally well defined.
- PrPSc, is the infectious form of the prion protein. Here Sc refers to ‘scrapie’, it is a prion disease that occurs in sheep. This protein is polydisperse and defined at a relatively poor level.
- This is the normal protein which is found in membranes of cells.
- It contains 209 amino acids and one disulfide bond.
- The molecular weight is about 35–36 kDa.
- It mainly appears in alpha-helical structure.
- There are present different topological forms of this protein such as; 1 cell surface form anchored via glycolipid and 2 transmembrane forms.
- This protein is not sedimentable means Centrifugation techniques cannot separate this protein.
- These proteins are bound copper (II) ions with high affinity.
- Proteinase K enzyme can readily digest the PrPc Protein.
- The enzyme phosphoinositide phospholipase C (PI-PLC) liberates this protein from the cell surface by cleaving the glycophosphatidylinositol (GPI) glycolipid anchor.
- This protein helps in cell-cell adhesion, intracellular signaling in vivo and may be involved in cell-cell communication in the brain.
- It is the infectious isoform of PrP or known as the prion.
- This protein can convert the normal PrPc proteins into abnormal infectious form by altering their conformation, or shape.
- Although the 3D shape of this protein is not clear, it assumed that it has a β-sheet structure.
Replication of Prion Protein or Mode of Action
There are two hypotheses on prion protein replication such as;
- Heterodimer model
- This is the first model to explain how prion proteins are replicate. According to this replication model, a single PrPSc molecule attached with a single PrPC molecule and then it catalyzes the conversion of PrPC to PrPSc.
- After that two PrPSc molecules combined with each other and can go on to convert more PrPC.
- Fibril model
- According to this model PrPSc appears as fibrils.
- The end portion of this fibril is combined with PrPC and converted into PrPSc.
Normal function PrP
- Regulated cell death
There are several prion-like proteins in our body such as MAVS, RIP1, and RIP3. This protein polymerizes into filamentous amyloid fibers and initiates regulated cell death.
- long-term memory: It helps to maintain long-term memory.
- Stem cell renewal: Studies of Whitehead Institute for Biomedical Research found that PrP is necessary for an organism’s self-renewal of bone marrow.
- Innate immunity: It plays a role in innate immunity and contains antiviral properties against many viruses, including HIV.
Types of Prion Diseases
1. Prion diseases in Human
- Creutzfeldt-Jakob disease (CJD)
- It is also called Subacute spongiform encephalopathy or Neurocognitive Disorder due to Prion Disease.
- CJD is a fatal degenerative brain disorder and was first discovered in 1920.
- The symptoms of this disease include memory problems, behavioral changes, poor coordination, visual disturbances, dementia, involuntary movements, blindness, weakness, and coma.
- In most of the cases this disease occurs spontaneously and in few cases it is inherited from a person’s parents.
- CJD has no treatment.
- Most of the cases this disease affects those people above 60 years old.
- This disease is classified as the transmissible spongiform encephalopathy.
- CJD can be transmitted through the contaminated harvested human brain products, corneal grafts, dural grafts, or electrode implants and human growth hormone.
- There are three types of CJD such as; Sporadic (sCJD), this occurs due to the spontaneous misfolding of prion-protein.Familial (fCJD), occurs by inherited mutation in the prion-protein gene. Acquired CJD, this can be occurred by direct contact with the contaminated tissue of an infected person.
- Gerstmann–Sträussler–Scheinker syndrome
- Gerstmann–Sträussler–Scheinker syndrome was first reported in 1936.
- It is a rare, usually familial, fatal neurodegenerative disease.
- This disease only affects patients from 20 to 60 years in age.
- It is classified as transmissible spongiform encephalopathies (TSE).
- The symptoms include progressive ataxia, pyramidal signs, and even adult-onset dementia.
- Fatal insomnia
- This is a rare disorder that results in trouble sleeping and it worsens over time.
- Other symptoms of this disease are speech problems, coordination problems, dementia and death.
- It occurs by the mutation of gene encoding protein PrPC.
- There are two forms of this disease such as fatal familial insomnia (FFI), which is autosomal dominant and sporadic fatal insomnia (sFI) which is due to an inherited mutation.
- This can be diagnosed by sleep study and PET scan.
- It is a very rare, incurable and fatal neurodegenerative disorder.
- This disorder is found in Fore people of Papua New Guinea.
- It is a transmissible spongiform encephalopathy (TSE).
- The symptoms include progressive cerebellar ataxia, or loss of coordination and control over muscle movements.
- The term kuru is a Fore word kuria or guria (“to shake”). Kúru itself means “trembling”.
- This disease is also called “laughing sickness”.
- Variably protease-sensitive prionopathy
- This disease is also known as Protease Sensitive Prionopathy.
- This disease is occurring in just 2 or 3 out of every 100 million people.
- The symptoms are speech deficits (aphasia and/or dysarthria) and progressive cognitive and motor decline (dementia, ataxia, parkinsonism, psychosis, aphasia and mood disorder).
- This disease only affects those people who are above 70 years.
Other diseases are include Familial spongiform encephalopathy, Iatrogenic Creutzfeldt–Jakob disease (iCJD), Variant Creutzfeldt–Jakob disease (vCJD), Familial Creutzfeldt–Jakob disease (fCJD), Sporadic Creutzfeldt–Jakob disease (sCJD).
2. Prion diseases in Animal
- It is a fatal, degenerative disease which affects the nervous systems of sheep and goats.
- It is a transmissible spongiform encephalopathies (TSEs).
- This disease is not transmissible to humans.
- The symptoms of this disease include lip smacking, altered gaits, convulsive collapse and compulsively scrape off their fleeces against rocks, trees or fences.
- The most effective way to prevent the transmission of scrapie disease is to quarantine and kill those affected.
- Bovine spongiform encephalopathy
- This disease is also known as mad cow disease.
- It is a neurodegenerative disease of cattle.
- The symptoms of this disease include abnormal behavior, trouble walking, and weight loss.
- The incubation time of this disease is four to five years.
- This disease can be transmitted to humans in the form of variant Creutzfeldt–Jakob disease (vCJD) by consuming contaminated food.
- Camel spongiform encephalopathy
- It is also known as mad camel disease and similar to mad cow disease.
- This disease affects camels.
- Chronic wasting disease
- It is also known as Zombie deer disease and is a transmissible spongiform encephalopathy (TSE).
- This disease affects mule deer, white-tailed deer, red deer, sika deer, elk, caribou, and moose.
- The symptoms of these diseases include chronic weight loss and clinical signs compatible with brain lesions, aggravated over time, always leading to death.
- This disease can be transmitted by consuming the brain, spinal cord, eyes, spleen, tonsils, lymph nodes of infected animals.
Other diseases include Spongiform encephalopathy (unknown if transmissible) affects Ostrich. Exotic ungulate encephalopathy (EUE) affects Nyala, Oryx, Greater Kudu. Feline spongiform encephalopathy (FSE) affects cats. Transmissible mink encephalopathy (TME) affects Mink.
Transmission of Prion Disease
Prion disease can be transmitted by this following methods;
- Acquired: When the individual has directly exposed to PrP contaminated food or medical equipment. If the person is exposed to urine, saliva, and other body fluids of infected animals.
- Inherited: The misfolded PrP can be produced by the presence of a mutation in a gene that codes for PrP.
- Sporadic: Misfolded PrP is formed without any causes.
Symptoms of Prion Disease
- Apathy, agitation, and depression.
- Thinking, memory, and judgment difficulty.
- confusion or disorientation.
- Myoclonus or involuntary muscle spasms.
- Ataxia or loss of coordination.
- Insomnia or trouble sleeping.
- difficult or slurred speech
- impaired vision or blindness
Diagnosis of Prion Disease
- Prion disease is difficult to diagnose because their symptoms are similar to other neurodegenerative disorders. Brain biopsy is the only way to confirm Prion Disease, but this process only can be performed after death.
- Currently, there are several tests which can be used to diagnose prion disease such as Magnetic resonance imaging (MRI), Cerebrospinal fluid (CSF) testing, Electroencephalography (EEG).
Treatment of Prion Disease
There is no effective treatment procedure for prion disease. Biologists are trying to find out an effective treatment for prion diseases.
Prevention of Prion Disease
- Don’t eat cattle from countries where BSE occurs.
- Don’t use the brain and spinal cord of a cow as a food.
- Don’t donate organs, blood if you are a prion patient, because blood is a good carrier of prion.
- Sterilize medical instruments that are recently coming in contact with the nervous tissue of someone with suspected prion disease.
- Currently, the Inherited or sporadic forms of prion disease can not be prevented.
Except animal and human prions are also found in fungi. These fungal prions help us to understand mammalian prions. Fungal Prions do not cause disease in their host body.