What are prions
The term prion originates from the English phrase proteinaceous infection particle. These are non-canonical agents that fundamentally differ from bacteria or viruses. Historically, prion diseases were classified among slow viral infections due to striking similarities in their clinical presentation. Today, however, science unequivocally classifies them as a distinct group of conformational diseases.
The primary problem caused by prions in the body is severe dysproteinosis, which is a disorder of protein metabolism leading to extensive neurodegeneration and destruction of nervous tissue.
Two forms of the prion protein
The development of the disease is directly linked to a change in the spatial structure (conformation) of a specific protein. There are two main forms of the prion protein (PrP):
- Normal (cellular) form — $PrP^c$.
The letter c stands for cellular. This is a completely normal, physiological protein of our body that is synthesized in cells and performs its everyday functions.
- Pathological (altered) form — $PrP^{sc}$.
The abbreviation sc comes from the word scrapie (a typical prion disease of sheep). This form differs from the normal one exclusively in its conformation. The change in three-dimensional structure turns a harmless protein into a lethal infectious agent.
Pathogenesis: conformational diseases
The pathogenetic essence of prion diseases lies in the molecular mechanisms of the cell. It is based on a gross disruption of the correct folding (folding) of the cell's own protein.
In a healthy cell, there are special helper proteins called chaperones. Their main task is to ensure the correct functional conformation for all newly synthesized proteins. In prion pathology, this well-regulated process is disrupted. Instead of the correct structure, the protein adopts an abnormal shape, which triggers a chain reaction of neurodegenerative changes.
Clinical Triad
The accumulation of the pathological protein and progressive destruction of the CNS determine the characteristic clinical picture. Regardless of the specific type of prion disease (whether in humans or animals), a classic clinical triad is always observed:
- CNS dysfunction. This primarily manifests as profound personality changes and cognitive decline.
- Movement disorders. Patients lose control over coordination and muscle tone.
- Fatal outcome. The disease progresses relentlessly; the duration of the clinical stage ranges from several months to several years, but always ends in death.
Briefly: answers to topical questions
What are the main functions of chaperones in the cell?
The main functions of chaperones are to ensure proper protein folding and maintain cell viability.
- Folding and reassembly — formation of the correct tertiary structure and correction of misfolded proteins.
- Protection against aggregation — prevention of premature folding and denaturation during stress.
- Transport function — keeping proteins in an unfolded state for transport across organelle membranes.
- Degradation — participation in the cleavage of unstable molecules and chaperone-mediated autophagy.
- Apoptosis regulation — control of programmed cell death.
- Thermotolerance — increasing the cell's resistance to thermal stress.
What are the main routes of transmission of prion infections in humans?
The main routes of transmission of prion infections in humans are divided into acquired, hereditary, and sporadic.
- Alimentary route — infection through consumption of insufficiently heat-treated meat or brain tissue from infected animals.
- Iatrogenic (medical) route — transmission via tissue transplantation (e.g., cornea), blood transfusion, use of animal hormones, catgut sutures, or insufficiently sterilized surgical instruments.
- Hereditary (genetic) route — transmission of mutations in the prion gene in an autosomal dominant manner.
- Sporadic route — overexpression of the normal prion protein and its transition into the pathological form.
Which animal diseases belong to prion pathologies besides scrapie?
In addition to scrapie in sheep and goats, animal prion pathologies include a number of other spongiform encephalopathies.
- Bovine spongiform encephalopathy (BSE) — known as "mad cow disease", transmitted alimentarily via infected meat-and-bone meal.
- Transmissible mink encephalopathy — a specific condition affecting minks.
- Chronic wasting disease — found in captive deer and elk.
- Feline spongiform encephalopathy — affects members of the feline family.
What methods of laboratory diagnostics confirm prion diseases?
Laboratory diagnostics of prion diseases are based on a combination of pathomorphological, immunochemical, and molecular-genetic methods.
- Pathohistological method — the "gold standard", requiring intravital or postmortem biopsy of CNS tissue to detect spongiform changes, astrocytosis, and amyloid in the absence of inflammation.
- Immunochemical methods — detection of protein markers in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA) and immunoblotting (IB) with monoclonal antibodies.
- Molecular-genetic methods — genetic analysis of the prion gene and polymerase chain reaction (PCR) to detect the prion protein.
Why are prions resistant to standard methods of disinfection and sterilization?
The resistance of prions to standard disinfection methods is due to their specific structural and physicochemical properties. The pathological prion is an altered isoform of the normal protein, characterized by a sharp increase in the proportion of $\beta$-pleated sheet structures (over 40%). Due to such conformational changes, the protein becomes hydrophobic and prone to aggregation, forming dense amyloid fibrils. As a result, the pathogen acquires extreme resistance to proteolysis, high temperatures, radiation, and chemical agents (including formaldehyde). Their destruction requires rigorous regimens, such as prolonged autoclaving at 134 °C or treatment with sodium hydroxide.
The triad of prion diseases is the rule of three "D"s: Dementia (CNS damage), Dyskinesia (motor disorders), Death (fatal outcome).
Class and exam questions
Why are prion diseases classified as conformational disorders?
Because they are caused by a change in the spatial structure (conformation) of the body's own protein from a normal to a pathological form.
What role do chaperones play in the development of dysproteinosis?
Normally, chaperones help proteins fold correctly. In prion diseases, this process is disrupted, leading to the accumulation of abnormal protein.
How do prions differ from the normal cellular protein?
The pathological $PrP^{sc}$ protein differs from the normal cellular $PrP^c$ protein exclusively in its altered spatial structure (conformation).
Why were prions previously confused with slow viral infections?
Due to the similarity of the clinical picture: both groups of diseases cause progressive CNS damage, have a long latent period, and inevitably lead to death.
What else to study on this topic
- Molecular differences in the structures of $PrP^c$ and $PrP^{sc}$
- Mechanism of action of chaperone proteins
- Similarities and differences between slow viral infections and prion diseases
- Pathogenesis of neurodegeneration in dysproteinoses
- Scrapie disease as a model for studying prions
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