Prions

By Vidyawini Ganapathy


Introduction

Prions are misfolded proteins that can transmit their misfolded shape onto normal variants of the same protein. The term ‘prion’ is derived from ‘proteinaceous infectious particle.’ The word was coined by Stanley B. Prusiner of the University of California School of Medicine at San Francisco in 1982.


Prion protein expressed in E. coli, purified and fibrillised at pH 7


It was discovered that prions are resistant to ultraviolet rays that break down nucleic acids, but are damaged by substances that disrupt proteins. This was explained by the prion hypothesis, which states that prion diseases are caused not by a conventional virus or bacterium, but by a protein that has adopted an abnormal form. It further states that the prion is the sole causative agent of prion diseases; no nucleic acid is involved.


Forms of the Prion Protein

The normal form of the protein is called PrPC; the C indicates ‘cellular’ PrP. The infectious form is called PrPSc, Sc referring to scrapie, a prion disease in sheep and goats.


PrPC

PrPC is found in cell membranes. It can be digested by Proteinase K, a protease.

Its function is not well understood, but research done on mice suggests that prion proteins play an important role in communication within the brain. The cleavage of these proteins causes the activation of myelin sheath repair in Schwann cells, which makes action potential propagation around 15 times faster than propagation in unmyelinated cells.

Evidence suggests that PrP expression on stem cells is necessary for an organism's self-renewal of bone marrow. The study showed that all long-term haematopoietic stem cells (cells that give rise to new blood cells) express PrP on their cell membrane. In addition, haematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.


PrPSc

PrPSc, found in infectious material, is a misfolded form of PrPC. It has a different structure and is highly resistant to proteases. It can convert PrPC into PrPSc by changing its shape, which in turn changes the way the proteins interconnect. This causes an exponential growth, because each PrPSc associates with PrPC and converts it to PrPSc, which further converts other PrPC proteins into PrPSc, and so on. The process by which this occurs is not fully known yet.

Aggregations of PrPSc form amyloid fibres, which have ends on to which other proteins attach; this leads to growth of the amyloid fibre. These amyloids are associated with tissue damage and death. One part of the prion protein can cause apoptosis (programmed cell death), which may explain why prion diseases cause neurodegeneration. Amyloids are also responsible for other neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease.

Amyloids are stable, making them resistant to denaturation (loss of secondary, tertiary and quaternary structure of the protein). This makes it hard to destroy these disease-causing fibres.


PrPres

Protease-resistant PrPSc-like protein, abbreviated as PrPres, is the name given to any isoform of PrPC that is strongly resistant to Proteinase K. Infectivity of the prion isoform and strong resistance to Proteinase K are not always correlated. Hence, the term ‘PrPres’ was coined to distinguish the Proteinase K-resistant prion from the prion disease-causing PrPSc.

Unlike PrPSc, PrPres may not be infectious.


Prion and Prion-like Diseases

Prion isoforms, or variants, of the prion protein present in the brain lead to transmissible spongiform encephalopathies (TSEs)—fatal conditions affecting the central nervous system (CNS) of animals like sheep, cattle and humans. These progressive neurodegenerative disorders have no known cure. Some TSEs include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt–Jakob disease (CJD) in humans.


Scrapie

Scrapie is a disease that affects sheep and goats. The first definitive record of the disease was in Great Britain in 1732. It is transmitted through direct contact between animals and through exposure to a contaminated environment. It is also postulated that it may be transmitted through the placenta of an infected mother to the offspring. Being a TSE, it is incurable and hence, it is necessary to quarantine and kill infected organisms to prevent further spread. The disease lasts for around one to six months.

Infected animals show pruritus—compulsive scraping of their fleeces against rocks or trees, which led to the disease being named ‘scrapie’. Other symptoms include lip smacking, altered gaits due to hindlimb ataxia (incoordination), convulsions and locomotor incoordination, which eventually progresses to death.


Bovine spongiform encephalopathy (BSE) / Mad cow disease

Bovine spongiform encephalopathy (BSE), or ‘mad cow disease’, affects cattle. It is the only zoonotic animal prion disease, i.e. it can be transmitted from an infected non-human animal to a person. It spreads from cattle to humans through consumption of contaminated meat, especially meat containing remnants of the animal’s brain, spinal cord or digestive tract. It causes variant Creutzfeldt-Jakob disease (vCJD) in humans. Meat and bone meals from other cattle with the disease are responsible for transmission between cattle.

Its extremely long incubation period—from 2 to 8 years—means that signs are not seen immediately. Some symptoms include abnormal gait (due to hindlimb ataxia), increased responsiveness to stimuli and low carriage of the head. Infected animals may also show aggression, anxiety and frenzy. These symptoms worsen until the animal goes into coma and subsequently dies.


Creutzfeldt-Jakob disease (CJD)

Creutzfeldt-Jakob disease (CJD) is a subacute spongiform encephalopathy or neurocognitive disorder due to prion disease that affects humans. The name ‘Creutzfeldt-Jakob disease’ was introduced by Walther Spielmeyer in 1922, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob.

Based on the reason for contraction of the disease, there are three categories:

Sporadic CJD: CJD is contracted even though the person is at no known risk for the disease. This is by far the most common type, with around 85% of all CJD cases being sporadic.

Hereditary CJD: The pattern of inheritance of CJD is autosomal and dominant, meaning that if a parent develops CJD, there is a 50% chance that their child would also develop the disease. Between 7.5–10% of cases are inherited.

Acquired CJD: This occurs when the disease is transmitted by exposure to an infected person’s brain or nervous system tissue, usually through certain medical procedures. There is no evidence that CJD is contagious through casual contact with someone who has CJD. Fewer than 1% of CJD cases are acquired.

About 70% of infected individuals die within a year. In the early stages of the disease, people may have failing memory, behavioural changes, lack of coordination, and visual disturbances. As the illness progresses, mental deterioration becomes pronounced and involuntary movements, blindness, weakness of extremities, and coma occur.


References

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