Prions

Stanley Prusiner 1982

Prions (proteinaceous infectious particles) are human glycoproteins consisting of 253 amino acids (molecular weight of 33-35 kDa) encoded by the prion protein gene (PRNP). Prions are physiologically present in both humans and animals.

However, when misfolded, prions can be restructured into a pathological, water-insoluble, heat-resistant, proteinase-stable beta-pleated structure. These pathologically folded disease-causing prions can be used in various applications. These pathologically folded pathogenic prions can cause various diseases of the central nervous system in humans and animals.

Prions are not living structures, but in the true sense only organic protein formations with virus-like (reproductive and infectious) properties. Pathogenic prions are fundamentally different from other pathogens such as viruses, bacteria or fungi because they do not contain DNA or RNA. However, they have the ability to transfer their pathological conformation to physiological prions.

The body's own prions are accentuated in brain tissue, so that pathological changes primarily affect this area. The pathogenic prions enter the body through contaminated food (e.g. in BSE). Other routes of infection are rather unlikely. Pathogenic prions can also be caused by mutations (e.g. familial variant Creutzfeldt-Jakob disease and familial insomnia).

Prions occur physiologically mainly on the cell surface (cell synapses) and protect the cells from bivalent copper ions, H2O2 and free radicals. Furthermore, it can be assumed that prions act as sensors in the cellular defence against reactive oxygen and free radicals and also influence the enzymatic degradation of free radicals. When physiological prions (PrP= prion protein) come into contact with a pathogenic prion - PrPSc- (PrPSc = Prion Protein Scrapie: pathogenic form of the prion protein first found in scrapie affected animals), the physiological prions restructure and take on the beta leaflet structure of the pathogenic prions ( PrPSc). The exact process of this "refolding" from PrPc to PrPSc is still unknown; however, the refolding occurs in such a way that further prion proteins can now attach themselves in a precisely fitting manner, just like two corrugated metal sheets lying on top of each other. The pathological prion proteins accumulate. Gradually, insoluble deposits are formed in the cells, so-called amyloid structures, which ultimately lead to the death of the infected cells.
Remarkably, this continuous chain reaction develops, in which more and more PrPC are converted into PrPSc (this puts this pathogenic process close to an infectious disease, but also close to other depositional diseases such as amyloidosis).

PrPSc with its beta-folded structure is less soluble in water (in contrast to the (physiological) alpha-helix, the hydrophobic chains do not point to the inside of the protein tertiary structure but are directed outwards); PrPSc is still heat-stable and is difficult for proteases to degrade.
Large amounts of deposited PrPSc have a destructive effect on the brain. This process of prion storage leads to cell death. Morphologically, "holes in the brain", sponge-like structures (spongiform encephalopathy) develop.

Route of infection: Animals and humans are usually infected with prions orally through food. The target organ of the prions where their pathogenic functions are affected is mainly the central nervous system. Since the disease has a long incubation period, it is assumed that the pathogen initially accumulates in certain "reservoirs" in the lymphoreticular system (spleen, lymph nodes), here mainly in the follicular dendritic cells.
After oral intake through food, prions can therefore also be detected in the Peyer's plaques, the lymphoreticular system (LRS) of the gastrointestinal tract. Remarkably, an intact immune system is a prerequisite for the accumulation and multiplication of prions. Immunodeficient mice in which the function of dendritic cells is disturbed are spared from the disease after intraperitoneal administration of infectious prions. The neuroinvasion is dependent on a neuroimmune interface. Possibly, the cell-cell transport of the prions takes place via exosomes, small cell vesicles with an average size of 50 to 90 nm. Many cell types are known to give off exosomes. These include the cells of the immune system, including monocytes and dendritic cells. The latter are known to play an important role in the spread of prions in the organism.

Prion diseases known so far:
Crapie, Transmissible mink encephalopathy (TME), Chronic wasting disease (CWD), Feline spongiform encephalopathy (FSE), Bovine spongiform encephalopathy (BSE), Exotic ungulate encephalopathy (EUE), Kuru, Creutzfeldt-Jakob disease (CJD), (New) variant Creutzfeldt-Jakob disease (vCJD, nvCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI)

Prions are extremely resistant to common disinfection or sterilization processes, but also to UV and X-rays (up to 25 KGy) as well as DNAsen and RNAsen. This was one reason for the BSE crisis. Today, based on the knowledge of the difficult inactivation of prions, there are strict regulations for the sterilization of material that may have come into contact with tissue containing prions.

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