You’ve probably heard of prion diseases before, even if you don’t recognize the term ‘prion’ or know the pathology behind them. Mad cow disease stirred the media into a frenzy in the past few decades, and Kuru is often mentioned in conjuncture with cannibalism. The cause of these diseases, prions are one of the most bizarre and fascinating pathogens around. They’re nigh indestructible and even prion ash is infectious. They’re pathogens that are nonliving, a trait which contradicts most biological disease lore. In a further twist, a single prion disease can be infectious, sporadic, and genetic—most diseases only have a single cause. So, what exactly is a prion and how does it cause these diseases? Surprisingly, it all comes down to a single, misfolded protein.
What is a prion?
The human body has around a hundred thousand types of proteins, which are often described as the building blocks of organisms. DNA, the genetic material in all cells, is used to make RNA, which is then translated into proteins: ribbons of amino acids. These ribbons fold according to various biochemical and physical laws into distinct and specific shapes that allow them to carry out their varied purposes, from structural to catalyzing chemical reactions . A mutation in a gene, a segment of DNA encoding a protein, can therefore completely change or disrupt the function of a protein and have disastrous consequences.
All humans, and most organisms, have the normal prion protein which is not pathogenic. This normal prion protein is encoded by a gene called PRNP on the 20th chromosome, and its role remains a mystery . The normal prion protein is found mainly in the central nervous system (your brain and spinal cord), but is also found elsewhere, including the peripheral nervous system and blood . It has proven tricky to study, with suggested functions ranging from neuronal cell differentiation, cell-to-cell recognition, signal transduction between neurons, response to oxidative stress, and the uptake of metal ions into cells[1,2,3]. However, the normal prion protein has a second possible configuration—often described as ‘misfolded’—which is both contagious and lethal . In these misfolded forms, prions become resistant to being broken down within the cell. A single misfolded prion protein is sufficient to cause a prion disease, because it spreads through what is called conformational influence: a prion will bind to a normal prion protein and cause the latter to also misfold, and so on, resulting in a cascade of infection that can move from cell to cell in a killer domino effect .
How do prions cause disease?
The neurotoxicity caused by these proteins is also not well understood, but it is clear that the presence of these proteins result in death in the form of spongiform encephalopathy, where cells in the brain die, resulting in the organ becoming similar to a sponge or Swiss cheese [6,8]. Consequently, prion diseases are classified as fatal, neurodegenerative diseases. The misfolded proteins cause progressive damage and cell death until the damage overcomes the body’s survival functions.
In genetic prion diseases, the gene for the prion protein has a mutation that increases the predisposition of the protein to misfold. In contrast, sporadic prion disease occurs when, due to some error in the process of protein making and folding, the prion protein misfolds spontaneously and begins the cascade of infection. In both of these cases, the prions are experimentally transmissible, resulting in the acquired or infectious form of prion disease: a misfolded prion enters the body, whether through oral consumption or via surgery or injection, comes in contact with the body’s normal prion proteins, and causes them to misfold. Prion diseases, especially acquired forms, have a long incubation period. It can take up to 40 years before disease symptoms start to show, due to a required threshold of misfolded prions, but death occurs within a year of the onset of symptoms .
Well that’s just fantastic. How can we treat prions?
While we don’t know exactly what the normal protein does, and we don’t understand exactly why the misfolded version kills cells, we do know that prions are one of the most frustratingly destruction-resistant pathogens out there. As prions are not alive, in contrast to the pathogens we encounter in almost all other infectious diseases (even viruses contain genetic material), killing them doesn’t actually work out very well. Radiation has no effect, formaldehyde makes them tougher, and only specific and highly concentrated types of bleach will dissolve them. They don’t die, so they can persist in soil or tissue samples for decades (we haven’t discovered a limit yet!). They bond to metal, such as surgical or dental equipment, which becomes a problem since the normal temperature such tools are sterilized at has no effect on them. They can be incinerated at high enough temperatures, but even then the ash is infectious (while not clearly understood—what a surprise—the theory is that a tiny bit of clay or silica holds the form of the prion after incineration and, if it comes in contact with an intact protein, will pass the conformation on).
There is no known or successful treatment to eliminate prions once they begin to spread through a person – the sheer difficulty in eliminating them hampers any attempt to cure the diseases that result. Their effectiveness as a contagious disease agent is stunning, especially as they are non-living which means they have not evolved to become successful pathogens. While other pathogens such as bacteria and viruses have developed over millions of years of selective pressures to become successfully virulent, prions have achieved a similar status as a byproduct of a spontaneous accident on the part of the human body. On the bright side, their sheer level of strangeness makes them a hot topic for research: in the past month alone, 77 articles have been published concerning prions.
An Interesting Side Note: Pronouncing “Prion”
Stanley Prusiner, the professor who showed that prions are nonliving proteins and coined their name (“a rather tortured acronym of ‘small proteinaceous infectious particle” – Nature), pronounced the term “pre-on.” However, the British, who were engaged in quite a bitter scientific rivalry over the nature of prions, pointedly pronounced it “pry-on.” Consequently, both pronunciations are frequently used .
 Ding, T. et al. “Cellular Prion Protein Participates in the Regulation of Inflammatory Response and Apoptosis in BV2 Microglia During Infection with Mycobacterium bovis.” J Mol Neuroscience. 2013 (Preprint).
 Hagiwara, K. et al. “Species-Barrier Phenomenon in Prion Transmissibility from a Viewpoint of Protein Science.” J. Biochem. 2013;153(2):139-145.
 Hartman, C. et al. “High Levels of Cellular Prion Protein Improve Astrocyte Development.” FEBS Letters. 2013;587:238-244.
 Head, Mark. “Human Prion Diseases: Molecular, Cellular, and Population Biology.” Neuropathology. 2013 (Preprint).
 Iwasaki, Y. et al. “An Autopsied Case of Creutzfeldt-Jakob Disease with Mutation in the Prion Protein Gene Codon 232 and Type 1+2 Prion Protein.” Neuropathology. 2013 (Preprint).
 Max, D. T. The Family That Couldn’t Sleep: A Medical Mystery. New York: Random House, 2006. Print.
 Younan, N. et al. “The Cellular Prion Proteins Traps Alzheimer’s AB in an Oligomeric Form and Dissembles Amyloid Fibers.” The FASEB Journal. 2013; 12-222588.
 Yusa, S. et al. “Cellular Prion Protein: From Physiology to Pathology.” Viruses. 2012;4:3109-3131.
 Zimowski, J. et al. “Hereditary Form of Prion Disease in Poland.” Neurologia I Neurochirurgia Polska. 2012; 46, 6:509-518.