One of the most gut-wrenching yet addictingly intriguing games I played growing up was Mafia. Sitting around a circle, discussing and debating the culprit…only for it to be the one person you thought was the healer!
The stealth and deception involved across the game reflect much more. Within our bodies, we see this play at a much larger scale across the immune system, manifesting as fevers, allergies, and other diseases. One prominent disease that often slips past our immune defenders, however, is prions. Our most secretive yet deadly macromolecules, prions, have the potential for immense harm but also surprising benefit.
But what exactly are they? Prions are a series of proteins that have become misfolded in a way that allows them to self-replicate, becoming independent of the cells in which they reside. They can be classified into three forms: prion proteins, responsible for forming prions, transcellular prionoids, misfolded proteins that aggregate through cell-cell interactions, and quasi-prions, anomalies in between prions and transcellular prionoids¹. Unlike viruses, bacteria, or even cells, prions are devoid of genetic material within their structure, with a mechanism of replication that varies based on how they have been misfolded. For instance, research on prions within the brain has shown that changes in electric charge may cause prion fibril elongation, leading the proteins to propagate and aggregate².
This aggregation mechanism often goes unnoticed by the immune system. As a biologically derived molecule, the prions are not viewed as foreign or antigenic by most immune cells. The most deadly is the neurodegenerative Creutzfeldt-Jakob disease (CJD), caused by overproduction of the prion protein, encompassing 85% of prion-disease forms in humans³. Variants of CJD spread dramatically due to mutation heritability and exposure to diseased tissue. In 1986, mad cow disease, a CJD that originated in cattle, spread to humans that ingested the meat, and was only controlled once infected herds were no longer consumed⁴. At a molecular level, it appeared that the abnormal prions in cattle were somehow modifying human prion development, indicating conserved mechanisms across species.
Prion disease manifestation can vary from person to person. CJD, for example, exhibits symptoms similar to many prevalent neurodegenerative diseases, making it hard to trace. Causing severe symptoms from confusion and dementia or hallucinations, the severe ailments that follow CJD still have very few treatment options⁵. Recent efforts have utilized a biotechnological approach to treating the disease, using tools such as gene editing with CRISPR-based tools, synthetic molecules and antibodies, and disinfectants⁶.
Like all biological phenomena, prions may have evolved to have unexpected positive effects. Due to their heritable nature, prions have the potential to pass on beneficial traits. A 2016 study at Stanford University found 46 prions in yeast cells that could improve the cell’s resistance to antifungals and heat⁷. With looser formations than their disease-causing counterparts, as well as a better affinity to DNA, these prions are more adaptable, ensuring better fitness of the cells containing these prions. Others like the CPEB prion-like proteins in the common fruit fly, Drosophila, have also shown potential to improve memory⁸.
For now, the legacy of prions in humans remains bleak. But could there be benefits to their existence? And, if we understand more prion-growth mechanisms, we might just alter our fundamental understanding of biology. This game of Mafia has just begun!
References
1. Harbi D, Harrison PM. Classifying prion and prion-like phenomena. Prion. 2014;8(2):161-165. doi:10.4161/pri.27960
2. UCL. Study reveals new detail on how prions replicate in neuronal cells. Brain Sciences. December 20, 2023. Accessed March 3, 2025. https://www.ucl.ac.uk/brain-sciences/news/2023/dec/study-reveals-new-detail-how-prions-replicate-neuronal-cells
3. Ritchie DL, Peden AH, Barria MA. Variant CJD: Reflections a Quarter of a Century on. Pathogens. 2021;10(11):1413. doi:10.3390/pathogens10111413
4. CDC. Bovine Spongiform Encephalopathy (BSE). Bovine Spongiform Encephalopathy (BSE). May 10, 2024. Accessed March 3, 2025. https://www.cdc.gov/mad-cow/php/animal-health/index.html
5. Prion Diseases. February 28, 2025. Accessed March 3, 2025. https://www.hopkinsmedicine.org/health/conditions-and-diseases/prion-diseases
6. Therapeutic Approaches for Prion Diseases | NIAID: National Institute of Allergy and Infectious Diseases. October 21, 2019. Accessed March 3, 2025. https://www.niaid.nih.gov/diseases-conditions/prion-therapeutic-approaches
7. Prions can pass on beneficial traits, study finds. News Center. Accessed March 3, 2025. https://med.stanford.edu/news/all-news/2016/10/prions-can-pass-on-beneficial-traits-study-finds.html
8.Prions: What Are They Good For? | Annual Reviews. Accessed March 3, 2025. https://www-annualreviews-org.ezproxy.rice.edu/content/journals/10.1146/annurev-cellbio-100913-013409#right-ref-B101