Normal cellular prion (PrPc)
The normal protein isoform is designated as $ ext{PrP}^c$ (cellular prion protein). In a healthy organism, this is a standard glycoprotein firmly anchored in the cell membrane.
- Structure and Properties: The molecular weight is 33–35 kDa. In its secondary structure, the protein contains very few $eta$-sheets (only about 3%). It is characterized by susceptibility to cleavage by protease enzymes.
- Distribution: The protein is found in the highest amounts in the tissues of the central nervous system. In addition, it is present in the spleen, follicular dendritic cells, lymph nodes, gastrointestinal tract, and skin.
- Biological Role: The protein is involved 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 (PrPsc)
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: The molecular weight is reduced to 27–30 kDa. Sharp conformational changes occur—the proportion of $eta$-sheet structures increases from 3% to 40% and more.
- Extreme resistance: The mutated protein is not destroyed by factors that kill ordinary microorganisms. It is resistant to high temperatures, ionizing radiation, formaldehyde, $eta$-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, so-called "plaques".
- Immunological tolerance: Since the pathological prion is of endogenous origin (it is the body's own altered protein), the immune system does not react to it. The infection proceeds without signs of inflammation and a 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, turning into $ ext{PrP}^{sc}$. Chaperone proteins (chaperon) 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 a 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 death.
Briefly: answers to topical questions
What morphological changes occur in nervous tissue during the accumulation of pathological prions?
When pathological prions accumulate in nervous tissue, spongiform degeneration develops without signs of inflammation. The main morphological changes include:
- Spongiosis — the appearance of multiple vacuoles in the neuropil and neurons, the fusion of which forms microcysts, giving the tissue a characteristic spongy appearance.
- Neuronal pathology — progressive vacuolar and hydropic dystrophy leading to cell death and diffuse atrophy of the cerebral cortex.
- Gliosis — reactive proliferation of glial elements (increasing astrocytosis).
- Amyloidosis — formation of prion-protein amyloid plaques containing the pathological protein.
Which specific human neurodegenerative diseases are caused by prions?
Prion diseases and prion-related human conditions in sources include:
- Creutzfeldt–Jakob disease.
- Kuru — an infectious form associated with ritual cannibalism.
- Gerstmann–Sträussler–Scheinker syndrome — a familial disease with cerebellar ataxia.
- Fatal familial insomnia — an inherited disease with progressive insomnia.
- Alpers' disease — a rare inherited chronic progressive encephalopathy with liver damage, developing predominantly in childhood and adolescence.
- Amyotrophic leukospongiosis.
- Spongiform myositis with prion-associated inclusions — a disease in which prion proteins, Ab-peptides, and apolipoprotein E are detected in muscle tissue.
Through what pathways does the transmission of prion infections to humans occur?
The transmission of prion infections to humans occurs via acquired and hereditary pathways. The main infection mechanisms include:
- Alimentary route — consumption of infected animal products (meat of sick animals), food supplements, or ritual cannibalism.
- Artifical (iatrogenic) route — infection during medical procedures. Includes the instrumental route (via insufficiently sterilized surgical instruments), transplantation (cornea, organ transplants), blood transfusion, and the drug route (administration of growth hormone or other animal-derived drugs).
- Hereditary route — transmission of the mutant gene in an autosomal dominant manner.
What laboratory diagnostic methods are used to detect prion infections?
A set of pathomorphological, immunochemical, and molecular genetic methods is used to detect prion infections. The main approaches include:
- Pathohistological examination — the "gold standard", involving intravital or postmortem biopsy of CNS tissue to detect spongiform changes, astrocytosis, and amyloid in the absence of inflammatory infiltrates.
- Immunochemical methods — examination of cerebrospinal fluid (CSF) using enzyme-linked immunosorbent assay (ELISA) and immunoblotting with monoclonal antibodies to detect specific protein markers.
- Molecular genetic methods — performing polymerase chain reaction (PCR) for the detection of the prion protein (PrP) and genetic analysis of the prion gene.
PrPc (Cellular) — Intact/normal protein. PrPsc (Scrapie) — Lethal/Broken.
Class and exam questions
Why is there no inflammation during prion infection?
The pathological prion is an altered isoform of the body's own protein, so the immune system does not recognize it as a foreign antigen.
Can prions be destroyed by standard boiling or proteases?
No. The pathological form is extremely resistant to high temperatures, proteolysis (including proteinase K), and chemical disinfectants (formaldehyde).
What is the main cause of neuronal death in prion diseases?
Accumulation inside cells of insoluble hydrophobic aggregates (amyloid fibrils) that disrupt neuronal function and give it a "spongiform" appearance.
What else to study on this topic
- The role of chaperone proteins in conformational changes
- The participation of the normal prion in copper metabolism
- The mechanism of formation of amyloid fibrils and plaques
- The morphological picture of neuronal death (spongiform appearance)
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