Normal Cellular Prion ($ ext{PrP}^c$)
The normal isoform of the protein is designated as $ ext{PrP}^c$ (cellular prion protein). In a healthy organism, it is a regular glycoprotein firmly anchored to the cell membrane.
- Structure and Properties: The molecular weight is 33–35 kDa. In its secondary structure, the protein contains very few $\beta$-sheets (only about 3%). It is sensitive to cleavage by protease enzymes.
- Distribution: The protein is found in highest amounts in central nervous system tissues. Additionally, it is present in the spleen, follicular dendritic cells, lymph nodes, gastrointestinal tract, and skin.
- Biological Role: The protein participates in vital processes: it regulates nerve impulse transmission, controls circadian rhythms, participates in copper metabolism in brain tissues, and regulates stem cell division processes in the bone marrow.
Pathological Prion ($ ext{PrP}^{sc}$)
The infectious form of the protein is designated as $ ext{PrP}^{sc}$ (scrapie prion protein). It is important to understand that this is not an extraneous virus or bacterium, but an isoform of one's own normal protein formed as a result of post-translational modifications.
Key features of the pathogenetic form:
- Altered Structure: Molecular weight is reduced to 27–30 kDa. Sharp conformational changes occur—the proportion of $\beta$-sheet structures increases from 3% to 40% or more.
- Extreme Resistance: The mutated protein is not destroyed by factors that kill ordinary microorganisms. It is resistant to high temperatures, ionizing radiation, formaldehyde, $\beta$-propiolactone, and enzymatic proteolysis (including proteinase K).
- Aggregation and Accumulation: The protein acquires hydrophobic properties and accumulates in plasma vesicles. It tends to form dense amyloid fibrils, known as plaques.
- Immunological Tolerance: Because the pathological prion is of endogenous origin (it is the body's own altered protein), the host immune system does not react to it. Infection proceeds without signs of inflammation and the classical immune response.
Mechanism of Replication (Proliferation)
Prion proliferation is not associated with the classical reproduction of microorganisms. The basis of pathogenesis is a disruption of kinetic equilibrium, in which the normal protein changes its spatial structure.
Stages of molecular conversion:
- Contact: The globular and hydrophobic pathological protein ($ ext{PrP}^{sc}$) interacts with the normal membrane protein ($ ext{PrP}^c$).
- Aggregation: Specific complexes—heterodimers—form on the cell surface.
- Transformation: Under the influence of the pathological form, the normal protein changes its tertiary structure, transforming into $ ext{PrP}^{sc}$. Chaperone proteins (chaperones) play an important role in this process of aggregation and correct (or incorrect) folding of the polypeptide chain.
- Chain Reaction: Having lost normal membrane proteins, the cell begins to actively synthesize new $ ext{PrP}^c$ molecules. These, in turn, are again drawn into pathological contact and transformed.
The result of this cascade is the massive accumulation of insoluble $ ext{PrP}^{sc}$ aggregates inside neurons. Neighboring structures become infected, and nerve cells acquire a characteristic "spongiform" appearance, which inevitably leads to their mass destruction.