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Prions (Spongiform encephalopathy)

Prions (Spongiform encephalopathy)


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Prions (Spongiform encephalopathy)

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USMLE® Step 1 style questions USMLE

2 questions

A 40-year-old man is brought to the emergency department by his partner due to rapidly declining cognitive function. The symptoms started four months ago. He has recently developed sudden, jerking movements in response to being startled. Past medical and family history is unremarkable. The patient does not take any medications. The patient immigrated to the United States from the United Kingdom (UK) in 1997. Vitals are within normal limits. Physical examination shows a depressed affect, significant for dysmetria, an ataxic gait, and a positive Babinski sign. Lumbar puncture shows elevated levels of 14-3-3 protein. The patient is admitted to the hospital for further evaluation. Four days into the hospitalization, the patient dies. A brain biopsy is performed, as shown below. Which of the following best describes the underlying pathophysiology of this patient’s condition?

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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.


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.