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What is the Link between Protein Folding and Prion Disease?

Written by The Protein Man | Aug 12, 2020 10:00:00 PM



Prion diseases (also referred to as transmissible spongiform encephalopathies, or TSEs) are a group of progressive, untreatable, and fatal neurodegenerative conditions affecting both humans and animals. Generally, these conditions are characterized by long incubation periods (usually between 5 to 20 years), disruption in the normal tissue structure (resulting in holes and vacuole formation in the neurons), and the absence of an inflammatory response.

 

Some of the most common examples of prion disease include Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, as well as kuru in humans, bovine spongiform encephalopathy (BSE or “mad cow disease”) in cattle, scrapie in sheep and goat, and chronic wasting disease (CWD) in deer, elk, and moose. Prion disease also affects cats (feline spongiform encephalopathy or FSE), camel (camel spongiform encephalopathy), ostrich, and mink (transmissible spongiform encephalopathy).

 

While these neurodegenerative diseases have long incubation periods, they progress rapidly once the symptoms – convulsions, balance and coordination dysfunction (ataxia), behavioral and personality changes, and dementia – start to show.

 

Prion diseases can be sporadic, infectious, or genetic in nature. Prions can enter the body through pathogenic transmission (e.g., when people or animals eat prion-contaminated food) or they can develop when the gene that codes for the protein undergoes mutation. There are also cases when the disease appears even when the person has no known risk factors for the disease.

 

Unfortunately, there is no known cure for prion diseases at present, and all cases ultimately lead to irreversible brain damage and death.

 

Protein Folding and Prion Disease Development: Understanding the Connection

TSEs are believed to be caused by “prions,” a type of protein that instigates the abnormal folding of normal proteins in the brain. While normal prion proteins (PrPc) are found throughout the body and are generally harmless, the problem starts when they come into contact with the misfolded, pathological isoform (PrPSc), which has a nasty reputation for making copies of itself.

 

Here’s what really happens when PrPc and PrPSc meet. Upon contact with PrPSc, the shape and conformation of normal prion proteins change. What was originally a flexible a-helical structure is stretched into a flat ß-strand. As a result, the way they interconnect with other proteins also changes.

 

The abnormally folded isoforms aggregate extracellularly in the central nervous system to form highly structured amyloid fibers whose ends are designed to attract free protein molecules. As the process continues, the amyloid fibers grow longer. Ultimately, they form plaques within the neurons and disrupt the normal tissue structure. Plaque formation brings about a significant increase in the number of astrocytes causing scar formation and the inhibition of axon regeneration in severe cases.

No one knows exactly how these proteinaceous infectious particles (prions) cause nearby proteins to collapse into the same abnormal three-dimensional configuration, although experts hypothesize that mutations in the PRNP sequence allows for the conversion of normal cellular prion protein (PrPc ) into PrPSc.

 

This is entirely possible, since PrPc and PrPSc have the same amino acid composition. They only differ in the manner by which the polypeptide chains are folded. While PrPc is made entirely of a-helical segments and is readily digested by proteinase K, PrPSc have more ß-sheets, making them highly stable and resistant to common denaturation processes using physical and chemical agents.

 

Moreover, PrPSc are also quite insoluble and insensitive to protease activity. This explains why they are extremely hard to dispose and contain. In fact, there is strong evidence proving that prions are not readily degraded in nature and can persist (and even accumulate) in the environment for years.

 

Interestingly, prions have another unique feature that sets them apart from other disease-causing vectors. They don’t seem to contain any genetic materials, i.e., DNA or RNA.