What are Prions?

Kaushik Bharati, PhD

Prions are infectious agents that are very unique compared to all other known infectious agents. This uniqueness stems from the fact that prions do not contain a nucleic acid genome that codes for their progeny. Moreover, the only known component of the prion is a modified protein that is encoded by a cellular gene. The best studied prion is the scrapie prion that causes the disease scrapie in sheep. Infected sheep lose coordination, tend to scrape (hence the name “scrapie”) or rub their skin, and eventually are unable to walk. Scientists have shown that scrapie is caused by an abnormal form of a cellular protein. The abnormal form is called PrP^Sc (for scrapie-associated prion protein), and the normal cellular form is called PrP^C (for cellular prion protein). 

Mechanism of Disease Induction

Prions cause a variety of neurodegenerative diseases in humans and animals. The fundamental event in prion diseases appears to be a conformational change that occurs during the conversion of PrP^C into PrP^Sc. PrP^C has been identified in all mammals and birds, but its function is unknown. PrP^C contains 45% α-helix and is virtually devoid of β-sheet. Conversion to PrP^Sc creates a protein that contains 30% α-helix and 45% β-sheet. Scientific evidence indicates that the PrP^Sc enters the brain and causes the PrP^C protein to change from its normal conformation to the abnormal form. The abnormal PrP^Sc protein molecules inhibit the enzyme proteasome 26S, leading to the vicious circle of further accumulation of the abnormally configured PrP^Sc protein, instead of the normally configured PrP^C protein. How the PrP^Sc causes the conformational change is unknown. However, the most plausible explanation, supported by evidence, is that the PrP^Sc directly interacts with PrP^C, causing the change. It is to be noted that mice lacking PrP gene cannot be infected with PrP^Sc. Although the evidence is strong that PrP^Sc causes PrP^C to fold abnormally, how this triggers neuron loss is unclear. Recent evidence suggests that the interaction of PrP^Sc with PrP^C serves to cross-link PrP^C molecules. The cross-linked PrP^C molecules bring about apoptosis or programmed cell death. Thus the normal, but cross-linked, protein causes neuron loss, whereas the abnormal protein acts as the infectious agent. As a result, there is accumulation of protein forming amyloid in the central nervous system (CNS), causing transmissible spongiform encephalopathies (TSE) in humans, sheep, cows and cats. The prion protein is not inactivated by cooking or conventional sterilization, and transmission is thought to occur by consumption of infected CNS tissue or by inoculation (e.g. via depth EEG electrodes, corneal grafts, cadaveric dura mater grafts and pooled cadaveric growth hormone preparations). The same diseases can occur in an inherited form, due to mutations in the PrP gene.

Prion Diseases: The Transmissible Spongiform Encephalopathies (TSEs)

Prion diseases such as TSEs include a number of conditions affecting both animals and humans, which are characterized by neuropathological features, including loss of neurons, spongiform appearance of the cortex and astrocytosis. Besides these changes there is amyloid plaque deposition. The amyloid is composed of the altered form (PrP^Sc) of the normally occurring (PrP^C) prion protein.

Diseases affecting animals include bovine spongiform encephalopathy (BSE) in cows (also known as ‘mad cow’ disease) and feline spongiform encephalopathy (FSE) in cats. Creutzfeldt-Jakob disease (CJD) is the most common TSE in humans which is very rare, with an incidence of 1 in million population globally, and usually occurs sporadically, but can also be transmitted by inoculation, as discussed above. About 10-15% of cases are inherited and arise from mutations in the PrP gene that codes for the prion protein.

Creutzfeldt-Jakob Disease (CJD): Sporadic CJD is generally seen in middle-aged to elderly people. Patients with CJD present with rapid progressive dementia, but 10% of patients exhibit cerebellar dysfunction initially. Other clinical features include myoclonus, a characteristic EEG pattern (repetitive slow wave complexes), visual disturbance and ataxia. These features are particularly seen in CJD that is transmitted by inoculation. Death occurs after a mean of 4-6 months. There is no effective treatment.

Variant Creutzfeldt-Jakob Disease (vCJD): It has been established that eating meat from cattle with BSE can cause a variant of CJD in humans (vCJD). vCJD differs from CJD in origin only: people acquire vCJD by eating contaminated meat, while CJD is an extremely rare condition caused by spontaneous mutation of the gene that codes for the prion protein. vCJD has been described in a small number of patients, mostly in the UK. The causative agent is the same as that isolated from ‘mad cows’ suffering from BSE. It is strongly believed that vCJD spread to humans by accidental consumption of contaminated beef during the BSE epidemic in Great Britain, which began in the early 1980s. Patients affected by vCJD are typically younger than those with sporadic CJD and present with neuropsychiatric changes and sensory symptoms in the limbs, followed by ataxia, dementia and death. Mean time of death is over a year, indicating that the progression of vCJD is slightly slower than CJD.

Other TSEs in Humans: Other extremely rare human TSEs include Gerstmann-Sträussler-Scheinker (GSS) disease, fatal familial insomnia (FFI) and kuru. While GSS disease and FFI occurs as a result of PrP mutation, kuru occurs due to infection. Kuru has been reported from Papua New Guinea in the Fore tribe who practised ritualistic cannibalism. The disease spread through the consumption of brains of dead tribal members. The disease occurs both in adults and children. Clinical features include progressive ataxia and dementia. The number of cases reported between, 1957-1982 was 2584. The disease has since disappeared following the banning of ritualistic cannibalism in Papua New Guinea.