How are prions generated? A study reveals the importance (or not) of cofactors.
When we think of infectious agents, most of us imagine viruses, bacteria, or fungi. However, there is another class of much more enigmatic and mysterious pathogens: prions. These misfolded proteins can cause devastating neurodegenerative diseases in humans and animals, such as Creutzfeldt-Jakob disease, scrapie in sheep, and bovine spongiform encephalopathy (also known as mad cow disease). One of the biggest mysteries in prion research is how their spontaneous misfolding occurs and what role cofactors play in this process.
A recent study, published in PLOS Pathogens by researchers from CIC BioGUNE, IRTA-CReSA, and the University of Santiago de Compostela, sheds new light on this phenomenon. The researchers explored how certain cofactors, such as polyanionic molecules, may facilitate the spontaneous misfolding of prions in the laboratory. Surprisingly, however, they discovered that these cofactors are not necessary for prions to become infectious.
How do prions form, and why are they dangerous?
Unlike viruses or bacteria, prions do not contain genetic material. They are an altered version of a normal protein found in brain cells, called PrP<sup>C</sup>, which, upon adopting an abnormal conformation, becomes PrP<sup>Sc</sup>. This misfolded protein can induce other normal copies to adopt the same erroneous structure, spreading like a domino effect.
Over time, prions accumulate in clusters that the brain cannot eliminate, leading to the progressive destruction of neurons. This results in severe neurological symptoms, cognitive decline, and, eventually, death. These diseases can arise spontaneously, be inherited, or be transmitted through contaminated food, such as in the case of mad cow disease in humans.
One of the biggest unanswered questions is how this spontaneous misfolding occurs, as most human cases are idiopathic, meaning they arise sporadically and with no known cause. Some researchers have suggested that certain molecules, known as cofactors, might play a role in this process, acting as catalysts or stabilizers of infectious prion forms.
The role of cofactors in prion generation
The study published in PLOS Pathogens investigated this question using an innovative experimental system called Protein Misfolding Shaking Amplification (PMSA). This in vitro model allowed researchers to generate mouse prions without the need for brain tissue, using only recombinant proteins and chemically defined cofactors.
Their findings showed that, while cofactors facilitate the conversion of the normal protein into a misfolded prion, they are not essential for prions to become infectious. Once a prion is formed, it can propagate its misfolded structure without the need for external factors. This challenges previous theories that suggested cofactors were indispensable for the generation of infectious prions.
The first author of the article, Dr. Miguel Angel Pérez Castro, during his stay at IRTA-CReSA, where he carried out part of the experiments that make up this publication.
Implications for prion disease research
This discovery has significant implications for prion disease research. It demonstrates that prions can arise spontaneously without the involvement of cofactors, which may help explain why sporadic cases occur in humans and animals. Additionally, it reinforces the idea that prion infectivity is not solely determined by its amino acid sequence but also by its structure and the conditions under which it forms.
In the future, this type of research could contribute to the development of treatments for prion diseases by identifying mechanisms to prevent or slow down protein misfolding. Furthermore, a better understanding of the factors influencing the formation of different prion strains could help predict how these diseases spread between species and their potential risks to public health.
A step forward in understanding prions
Although there is still much to learn about prions and the mechanisms governing their formation, this study represents an important advance. The ability to generate infectious prions under controlled conditions without the need for cofactors opens new avenues of research in this field.
This study was conducted by researchers from CIC BioGUNE, IRTA-CReSA, the University of Santiago de Compostela, and other institutions, and was published in PLOS Pathogens:
Pérez-Castro MA, Eraña H, Vidal E, Charco JM, Lorenzo NL, Gonçalves-Anjo N, et al. (2025) Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions. PLoS Pathog 21(1): e1012890. DOI: 10.1371/journal.ppat.1012890.
This work was partially funded by:
Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación del Gobierno de España, project numbers PID2021-122201OB-C21/C22 and PID2020-117465GB-I00.
Project EFA031/01 NEURO-COOP, co-financed (65%) by the European Union through the Interreg VI-A Spain-France-Andorra Program (POCTEFA 2021-2027).
