Prions (Spongiform encephalopathy)

Definitions & Key takeaways

Spongiform encephalopathy is a neurodegenerative brain disease caused by the accumulation of misfolded prion proteins. This degeneration gives the brain a spongy appearance, hence its name. Prions can be transmitted by eating infected meat, blood transfusion, corneal transplants, and contaminated surgical instruments. There is no treatment for spongiform encephalopathy and they always result in dementia and eventually death.

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Spongiform encephalopathy can be broken down. Spongiform means sponge like, encephalo- refers to the brain, and -path refers to a disease process.
So spongiform encephalopathy is a disease where the brain tissue degenerates and healthy tissue gets replaced by clusters of tiny liquid filled, thin-walled cavities called cysts, making the brain look like a sponge.
The underlying cause of spongiform encephalopathy is the accumulation of misfolded proteins called prions. First, let’s review a bit.
Proteins are made up of a long string of amino acids, and the exact sequence of these amino acids is called the primary structure.
These long chains of amino acids can fold to form different shapes, like an α-helix which is a right-handed coiled strand and a ß pleated-sheet which is when the chain folds so that segments line up alongside one another.
Each protein can contain multiple α-helices or ß pleated-sheets. Now, there’s a protein called Prion protein, or Prp, which is encoded by the PrNP gene.
This protein is 253 amino acid long and is made up of mostly α-helices. It’s most commonly found on the cell membrane of neurons.
Although the function of Prp is unknown, it’s thought that it might play a role in synapses between neurons and the uptake of copper into the cell.
When a prion protein is misfolded, it changes from mostly having α-helices to having a lot of ß pleated-sheets. This new abnormal protein is called a “prion”.
When the misfolded protein enters the cells of the nervous system and interact with the normal prion protein, it acts as a template and induces misfolding in the normal prion proteins.
These prions are also highly resistant to being broken down by proteases, which are the enzymes that break down abnormal proteins.
As a result, these misfolded prion proteins cannot be easily broken down, they cause normally folded proteins to misfold and become like them, and they have an affinity for the brain - they’re basically like little ß-sheet filled zombies.
The misfolded prions accumulate within the cell and they trigger apoptosis, which is programed cell death. This is done with the help of 14-3-3 protein which is an intracellular protein that promotes apoptosis .
When large numbers of cells start to die off, cysts begin to form in the brain, and over time, this gives the brain it’s spongy appearance.
Additionally, the prions aggregate together on the membrane of the neurons, forming large plaques that are toxic to brain tissue.
Now, the most common cause of spongiform encephalopathy is Creutzfeldt-Jakob disease or CJD. And there are actually four types of CJD; familial or fCJD, variant or vCJD, iatrogenic or iCJD, and sporadic or sCJD.
All four types cause spongiform degeneration of the cerebral cortex and cerebellum. Familial Creutzfeldt-Jakob’s disease occurs when there’s a mutation in the PRNP gene.
The most common mutation occurs at the 200th codon and causes the amino acid glutamic acid to be replaced by a lysine, and that’s enough to make the entire protein misfold.
Variant Creutzfeldt-Jakob’s disease is caused by eating the meat of cows with prions in the muscle tissue. In cows, these prions cause bovine spongiform encephalopathy, which is more commonly called “Mad cow disease.” When sheep are fed cow meat, the prion causes the disease Scrapie.
If a person eats the meat of affected cows or sheep, the prions get absorbed through the intestines and get absorbed into the bloodstream.
After that things get a bit unclear. It’s thought that the protein can somehow get through the blood brain barrier and then enters neurons by a process called adsorptive endocytosis.
Adsorptive endocytosis is a process where the plasma membrane of nerve cells folds inwards to bring in substances that otherwise would not be able to cross the plasma membrane by themselves.
Furthermore, since the misfolded proteins are in the blood of individuals with variant CJD donate, if they try to donate blood, the prions can get transmitted to recipients of the blood and that can spread the disease.
In fact people in the UK who have received a blood transfusion since January 1980 are banned from donating blood for that reason!
Iatrogenic Creutzfeldt Jakob disease is caused by medical procedures, like when equipment for a procedure like a corneal transplant gets contaminated and infects healthy individuals.
Finally, there’s sporadic Creutzfeldt-Jakob disease which pops up in populations randomly without a clear cause. This could be due to a spontaneous mutation in the 129th codon in the PRNP gene that replaces valine for a methionine.
People with this mutation are more likely to develop sCJD and are also more susceptible to vCJD. Another type of spongiform encephalopathy is Kuru, which is spread through cannibalism of infected flesh - in other words, when an individual eats the human flesh of an infected individual.
Kuru famously affected a tribe in New Guinea who ate the brains of deceased family members. And in this way, the misfolded prion proteins pass from person to person.
Since the symptoms are similar to those of CJD, it is suspected that Kuru started when one of the tribes people acquired sCJD.
Another disease is fatal familial insomnia which is also caused by a mutation in the PrNP gene at codon 178 where aspartic acid is substituted with asparagine - an interesting example of two different clinical diseases developing from different mutations in the same gene.
In fatal familial insomnia, misfolded prion proteins build up mainly in the neurons of the thalamus that help regulate sleep rather than causing the typical spongiform degeneration of the cerebral cortex and cerebellum that occur in other prion diseases.
Symptoms of spongiform encephalopathy might not show up for decades after prions have entered or formed in the body, but once symptoms start developing they tend to progress rapidly resulting in death within a year.
Early symptoms for CJD and Kuru involves motor symptoms like ataxia, which is defined as lack of coordination of voluntary movements, and neurological symptoms like poor memory, and behavioral changes.
Later stage symptoms include muscle weakness that makes it difficult to walk or stand, and myoclonus or quick, jerky movement of the muscles; hiccups are an example of myoclonus.
Finally there’s dementia which is where a person loses their mental functions like memory, decision making, and reasoning.
Lastly, in fatal familial insomnia, people present with early symptoms of insomnia and exaggerated startle response in the early stages.
Eventually they can not sleep at all and can experience hallucinations. Like the other prion diseases, they eventually develop dementia and death.
Spongiform encephalopathy is diagnosed based on symptoms and MRI findings which include lesions in the cortex, basal ganglia, and thalamus.
A lumbar puncture can also be done to obtain cerebrospinal fluid which might show an elevated levels of 14-3-3 protein and is a sign of significant neuronal destruction.
Ultimately, the definitive diagnosis of spongiform encephalopathy is done with a brain biopsy which is typically done after a person dies.
There are currently no treatments for prion diseases. Supportive care should be given and genetic counseling should be offered for those with familial forms of the disease.
It is best to prevent transmission of the prions by restricting blood donation from those with the disease and thoroughly decontaminating surgical equipment.
All right, as a quick recap, spongiform encephalopathy is a degenerative brain disease caused by the accumulation of misfolded prion proteins.
This degeneration gives the brain a spongy appearance and is seen in diseases like Creutzfeldt-Jakob disease and Kuru. Prions can be transmitted by eating infected meat, blood transfusion, corneal transplants, and contaminated surgical instruments.
There is no treatment for these disease and they always result dementia and eventually death so prevention of transmission is the key management strategy of the disease.