In an interview with PAP, the researcher explains how misfolded proteins spread through the brain, why they pose challenges for modern medicine, and what scientists hope to learn from studying them.

PAP: When I realize how prions work, it chills my blood. Misfolded proteins - effectively dead molecules that lack DNA or RNA - have the ability to multiply in the body at the expense of structurally sound molecules and cause disease? A scenario straight out of a zombie movie.

Professor Beata Sikorska: I will give you even more reasons to worry. There is growing evidence that all neurodegenerative diseases have biology similar to prion diseases. Conditions like Alzheimer's disease can also be, in a sense, transmissible. The word "infectious" is a strong word, but there is a risk of transferring pathological proteins from one patient to another, for example, through neurosurgery. The mechanism that seemed unique to prions also applies to other proteins.

PAP: Before we move on to Alzheimer's disease, let us try to understand: what are prions?

B.S.: The body produces natural proteins necessary for brain function, among other things. Under certain conditions, they change their secondary structure (the way they fold in space) though their chemical composition remains unchanged. However, assuming a new spatial form completely alters their properties.

This makes these proteins highly resistant to enzymes, and their most important characteristic is the ability to "infect" healthy molecules of the same type of protein with their folding pattern. When such an abnormal protein comes into contact with a normal form, it causes a change in the structure of the encountered protein. Therefore, there are fewer and fewer normal molecules in cells, and more and more abnormal ones.

Such infectious, misfolded protein molecules are called prions, and their correct counterpart is prion protein (PrP).

Incidentally, giving these specific, misfolded proteins a separate name - prion - was a move recommended by PR experts to Stanley Prusiner, who was hoping for a Nobel Prize. It did help him. He received the Nobel Prize for prions in 1997.

PAP: What mechanisms are common to human prion diseases: the most common Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI)?

B.S.: These are rare brain diseases from the family of transmissible spongiform encephalopathies. The accumulation of abnormal protein leads to neuronal dysfunction, which gradually impairs brain function. The abnormal prion protein polymerises, forming fibrils that accumulate in synapses and form structures called amyloid plaques, similar to Alzheimer's disease, although in each of these diseases, these plaques are composed of different proteins. However, this process is very long. The incubation period for prion diseases can range from 10 to 40 years.

PAP: Where do the first prions in the body come from?

B.S.: In the case of Creutzfeldt-Jakob disease - we have about 40 cases per year in Poland - there are three pathways for the development of the abnormal protein. The first, most common, is the spontaneous transformation of a normal protein into an abnormal one; we do not yet fully understand why this occurs.

The second pathway is the introduction of a particle from outside, for example, through the consumption of infected meat, or iatrogenic cases, ones that result from medical procedures.

The third pathway is genetic mutation; hereditary forms account for approximately 15% of prion disease cases.

PAP: How can prion diseases be transmitted during medical procedures?

B.S.: Most cases were caused by the administration of pituitary hormones and dura mater grafts from deceased donors. Currently, we are concerned about transmission during laboratory work and neurosurgical procedures. This is particularly true for instruments used during neurosurgical procedures, as - when it comes to prions - nervous tissue is the most infectious.

Standard sterilisation, including autoclaving, does not destroy prions. Prions are extremely resistant, they only decompose at temperatures of 1000 degrees Celsius. To effectively neutralize them, instruments must be treated with concentrated sodium hydroxide (NaOH) or formic acid before autoclaving.

The problem is that to use these procedures, we must be aware that we have just operated on a patient with prion disease. This is difficult, because the pathological protein spreads asymptomatically for a long time.

In the history of medicine, cases of prion infections have also been documented as a result of the use of growth hormone obtained from the pituitary glands of deceased donors in the 1970s and 1980s, or blood transfusions from people with a variant of Creutzfeldt-Jakob disease (vCJD) during the asymptomatic period. In the case of the vCJD variant (infection occurs by eating meat from cattle infected with mad cow disease), lymphatic tissue is also infectious, which means the presence of prions in the blood and even in the digestive tract. Performing a gastroscopy or colonoscopy on an infected person could contaminate the equipment.

PAP: Can prion diseases be treated?

B.S.: Current attempts are not very effective. The greatest hopes are associated with monoclonal antibodies that would capture and block the pathological form of the protein. Antisense oligonucleotides (ASOs) and siRNA technology are also being tested to reduce the expression of the normal protein. However, all this is at the early research stage.

We would have to start such treatment preventively before brain damage occurs. And that would be difficult for now. Monoclonal antibodies are not neutral, they can cause, for example, damage related to the immune response, as we know from research on Alzheimer's disease, and they can also be neurotoxic.

PAP: Is Alzheimer's disease a prion disease?

B.S.: We know pathologically folded proteins: tau and amyloid beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It was experimentally determined that they can show the same mechanism of conformation change by contacting the normal and pathological forms.

Nobel Prize winner Stanley Prusiner even advocates the use of names such as "Alzheimer prions" or "Parkinsonian prions". However, the medical community is sceptical about this. We mostly use the name "misfolded proteins".

We do not want to use the name prions, because prions are clearly infectious, and other neurodegenerative diseases are not infectious in the classical sense. The most we can say is that these proteins have the "ability to propagate".

In the case of Alzheimer's disease, there is no evidence of a symptomatic disease transmitted from person to person. However, we have evidence that the administration of pituitary hormones or dural transplantation may result in the transmission of misfolded protein, which leads to its multiplication in the recipient. However, we have no evidence that as a result of such transmission, a human has developed a symptomatic disease.

However, it was possible to transfer Alzheimer's disease from humans to mice in laboratory conditions. Pathological beta amyloid was extracted from the brain of a man who had died of Alzheimer's and administered to mice, and the protein began to spread and cause disease symptoms.

PAP: Should hospitals introduce stricter procedures because of the risk of transmitting misfolded proteins?

B.S.: International symposia are increasingly calling for stricter treatment of surgical instruments, also in the case of neurosurgical operations on patients with diseases such as Alzheimer's disease. Such recommendations already appear in the scientific literature. Whenever possible, we use disposable tools, which we immerse in NaOH or burn at high temperature before disposal.

PAP: What is the Prionomics project?

B.S.: Our consortium consisting of seven centres collects samples of cerebrospinal fluids, blood and even tear fluid, as well as autopsy tissues from people with prion diseases. The project focuses on the study of the so-called omic data (genomic, transcriptomic, proteomic) and the search for new genetic and proteomic markers, and our primary goal is to find biomarkers that would allow for early, pre-symptomatic detection of the disease process. The main obstacle is the rarity of these diseases, which is why we try to collect data from many countries. The PRIONIER consortium and the International CJD Surveillance Network were established for a similar purpose.

PAP: What would you like readers to remember about prions?

B.S.: First of all, the infectious agent may be a protein particle without nucleic acid.

Secondly, this mechanism probably constitutes a universal matrix for all neurodegenerative diseases. If we want to tame diseases that affect millions of people around the world, we need to thoroughly understand how proteins change their conformation and damage the nervous system as a result of contact with pathological molecules.

The people who deal with prions are a small group of true enthusiasts. Research in this direction is not driven by big money or quick successes, but by the prospect of solving one of the greatest mysteries of modern medicine.

Interview by Ludwika Tomala (PAP)

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