The Pressing Issue of the Prion
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Among other macromolecules, proteins are one of the most crucial building blocks of life. They aid in a number of biological processes, such as DNA replication, and are a major component of the physical human body, forming our hair, nails, and nearly 80 percent of our muscle mass. They also play an important role in the brain, where they form connective tissue and aid in a number of neurological processes. The consequences are terrifying, then, when a slight folding mistake alters one protein entirely.
Enter prions, or infectious, misfolded proteins. Their altered conformation gives them a number of frightening features, including but not limited to the ability to induce other proteins to misfold. The nonpathogenic version of a prion is a 250-amino-acid-long “proteinaceous infectious particle” (PrP), whose misfolding is centrally involved in the transmission of all known prion diseases.
As with all biological macromolecules, the prion is a prime example of the link between molecular structure and function. With an unaltered structure, PrP can carry out its biological processes without fail. Spontaneous mutations affecting the genes that code for PrP directly affect which amino acids are used to synthesize the protein. This shift in the fundamental formation of PrP leads to an avalanche of molecular effects which eventually culminates in a dangerously misfolded infectious protein—a prion.
This prion is responsible for the classic Creutzfeldt-Jakob Disease (cCJD), a progressive genetic neurodegenerative disorder. Variant Creutzfeldt-Jakob Disease (vCJD) is essentially the human version of mad cow disease. Both neurodegenerative diseases are classified as transmissible spongiform encephalopathies and result in the accumulation of prions in the cerebrum and the cerebellum, parts of the brain responsible for sensory and motor coordination, balance, and higher cognitive processes. The deadly protein beta-amyloid (characteristic of Alzheimer’s Disease) also forms fibers as it polymerizes and aggregates into plaques. In both Alzheimer’s Disease and CJD, patients progressively lose their cognitive abilities as the amyloid fibers disrupt brain tissue and connectivity. This also gives the patient's brain the characteristic “spongy” appearance.
Both forms of Creutzfeldt-Jakob Disease are fatal, with most victims dying approximately one year after contracting the prion. Sporadic CJD is responsible for approximately 85 percent of all cases, where a person has no known risk factors for the disease. The remaining 15 percent of cases occur as a result of inherited mutant variants of the PRNP gene responsible for CJD and consumption of beef contaminated with mad cow disease. Person-to-person transmission of the disease is rare and the primary cause for the spread of prions is through contaminated medical equipment.
Prions have historically been transmitted through medical equipment such as neurosurgical tools, corneal grafts, growth hormones, and human dura matter (the tough outer membrane of the brain that protects softer inner tissue). Thankfully, each of these recorded cases occurred before 1976, the year when sterilization standards were implemented in all healthcare practices. Despite the adoption of sanitization methods, the transmission of prions through medical equipment introduces another of the prion’s frightening traits: they are extremely stable.
In order to effectively neutralize prions, they must be denatured, with their unique folding pattern disrupted to the point where they cannot continue to transmit their conformation onto other healthy proteins. Protein folding is organized by several structural classifications such as primary and secondary structures. The primary structure is a protein’s amino acid sequence while its secondary structure is formed by hydrogen bonds between those amino acids, taking the form of alpha helices, visually described as curls, or beta pleated sheets. The folding of prions, however, is such that their alpha helices and beta pleated sheets render ordinary methods of denaturing proteins useless, and they remain transmissible even after exposure to conditions that would denature normal proteins.
A study performed on sheep infected with the TSE disease scrapie indicated that after 16 years, the scrapie prion remained highly infectious. A hallmark of the prion’s unique conformation is its resistance to proteolysis, or the destruction of protein structures. The most reliable method of destroying prions is exposing them to nearly 1,000 degrees Celsius of heat, with any exposure below 600 degrees allowing the prion to maintain low infectivity. Such high temperatures are unsustainable and typically inaccessible to those who need to eradicate prion exposure.
One of the proposed solutions for removing prions involves destroying the expensive heat-resistant equipment. However, this method of preventing transmission is not the most cost effective. The cleaning solutions specified for destroying TSEs on surgical equipment—namely, sodium hypochlorite and sodium hydroxide—often release toxic fumes and corrode the equipment. Thus, they too are not the most effective methods of preventing transmission.
Despite the relative rarity of prion diseases, their progressive, incurable, and misfolded nature are of interest to scientists. Their unique structure compels scientists and researchers to focus more on proteins, studying the relationship between their structure and function to explore questions about their ability to transfer their conformation to healthy proteins. Studying the mechanisms of prion diseases also gives insight into protein folding as a whole, giving researchers an opportunity to develop treatments for other protein-based diseases like cystic fibrosis. Research on prions is still in its infancy, but as it progresses, we are sure to understand one of the building blocks of nature better than ever before.