7 Prions
Prions are unusual infectious agents associated with a number of human, animal and fungal diseases. In humans they can cause degenerative changes in the brain: the transmissible spongiform encephalopathies. Kuru is the classic example of such a condition, epidemiological studies confirming human–human transmission. Prions lack a nucleic acid genome and are highly resistant to all conventional forms of disinfection processes. They are small proteinaceous particles that are modified forms of a normal cellular protein, and cause disease by converting normal protein into further abnormal forms. Prion-related conditions can arise endogenously by mutation (and be inherited) or be acquired exogenously during medical procedures or by ingestion of contaminated material. The prion diseases are part of a spectrum of neurodegenerative disorders in which soluble proteins are modified and accumulate as insoluble beta-sheet rich amyloid fibrils. The other neurogenerative disorders that include different types of dementia are not infectious but are sporadic or inherited, sharing a common pathogenesis. Endogenous sporadic Creutzfeldt–Jakob disease (CJD) has been known for some time as have Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia and kuru. However, in the 1990s another form of this disease (variant CJD, vCJD) was associated with eating beef from cattle infected with the prion that causes bovine spongiform encephalopathy.
‘Rogue protein’ pathogenesis
Prions are unique infectious agents
There are a number of human and animal diseases – the spongiform encephalopathies – whose pathology is characterized by the development of large vacuoles in the CNS. These include kuru and Creutzfeldt–Jakob diseases (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. Sporadic CJD is the most common prion disease in humans worldwide and the incidence is approximately 1.5 per million people. For a long time, these diseases were thought to be caused by so-called unconventional slow viruses, but it is now known that the agents concerned are prions; small, proteinaceous infectious particles. Their characteristics include:
• small size (< 100 nm, therefore filterable)
• lack of a nucleic acid genome
• extreme resistance to heat, disinfectants and irradiation (but susceptible to high concentrations of phenol, periodate, sodium hydroxide, sodium hypochlorite)
• slow replication – typically diseases have a long incubation period and usually appear late in life. Incubation periods of up to 35 years have been recorded in humans, but variant CJD can produce symptoms much more rapidly
Prions are host-derived molecules
Studies on scrapie gave some insight into the nature of prions and their role in disease. The infectious agent is a host-derived 30–35 kDa glycoprotein (termed PrPSc, prion protein scrapie) that is associated with the characteristic intracellular fibrils seen in diseased tissue. PrPSc is derived from a naturally occurring cellular prion protein (PrPc), expressed predominantly on the surface of nerve cells and coded by a single copy gene of unknown function (located on chromosome 20 in humans). Mice with the PrPc gene disrupted are resistant to scrapie, and they show no gross abnormalities. The two proteins have a similar sequence, but differ in structure and protease resistance; PrPSc is globular and enzyme resistant; PrPc is linear and enzyme susceptible. The association of PrPSc with PrPc results in conversion of the latter into the abnormal form, the change being largely conformational, from alpha helices to beta-pleated sheets. Affected cells produce more PrPc and the process is then repeated, the accumulating PrPSc aggregating into amyloid fibrils and plaques (Fig. 7.1). Replication can lead to very high titres of infectious particles and up to 108–109/g of brain tissue have been recorded.
Figure 7.1 How prions may damage cells. (1) Normal cells express PrPc at the cell membrane as linear proteins. (2) PrPSc exists as a free globular glycoprotein, which can interact with PrPc. (3) PrPc is released from the cell membrane and is converted into PrPSc. (4) Cells produce more PrPc and the cycle is repeated. (5) PrPSc accumulates as plaques, and is internalized by cells.
Evidence that the interaction of PrPSc with PrPc causes these events is based on extensive experiments in sheep and mice, the main conclusions being:
• Scrapie infectivity in material co-purifies with PrPSc.
• Purified PrPSc confers greater scrapie activity.
• Mice lacking the PrPc gene do not develop disease when injected with prions.
• Introduction of a PrP transgene from a prion donor species (e.g. hamster) into a recipient species (e.g. mouse) facilitates cross-species transmission, suggesting that homology between the PrP genes of donor and recipient is the main molecular determinant of such transmission.
• In vitro, PrPSc can convert PrPc into PrPSc, with the transfer of biochemical characteristics.
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