Prions — Definition, Diseases, Structure and diagnosis

 Prion is a proteinaceous infectious agent that causes fatal degenerative disease of nerves. Prions can be genetic, infectious or sporadic disease. The protein is able to structurally transform a normal occurring protein into an abnormal structural protein that is transmissible to other prion proteins. They are the main cause of transmissible spongiform encephalopathies.

Overview: 

Prions cause bovine spongiform encephalopathy in cow, which is commonly referred to as mad cow disease, scrapie in sheep and are also suspected to cause chronic wasting diseasein deer.

In humans, they can cause Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, kuru, and Gerstmann-Sträussler-Scheinker syndrome. Multiple system atrophy is caused by misfolded alphasynuclein and therefore it is also classified as a prion disease.

When prions affect a healthy individual, they cause properly folded proteins to convert into amyloid form, in which proteins convert into aggregated beta pleated sheets, which accumulate which has potential to damage to the brain if accumulated in abnormal quantities.

The structure of the prion protein is remarkably stable and they are resistant to denaturation. It is therefore difficult to dispose of the infectious material.

Incubation Period of Prion Protein

The incubation period can be determined by the growth rate at which the prion proteins replicate. The propagation depends on whether the animal possesses a normal prion protein or not. Animals that do not have the normal prion protein cannot develop or transfer the disease to others. The disease can infect women and children, with the symptoms of tremors, coordination problems regarding arm and leg pain, and headache.

Discovery of Prion Proteins

Two London based researchers, Tikvah Alper and John Stanley Griffith, hypothesized that some transmissible spongiform encephalopathies are only caused by proteins. They also suggested that the agent causing spongiform encephalopathies and Creutzfeldt Jakob disease was not affected by radiation because the particle was too small to be hit by ionizing radiation. Later in 1982, Stanley B. Prusiner and his team managed to isolate the protein after two years and they said that the infectious agent is purely a protein. They also stated that the prion protein can occur in a normal as well as an infectious form.

Structure of Prion Proteins

The prion proteins are essentially present throughout the body in humans and in animals. However, the prion protein found in infections has a different structure and is resistant to proteases. Their entry to the brain happens through infection resulting in the progressive break down of neuron causing prion diseases. All prion proteins are not infectious.

Following are the different forms of prion proteins

1. PrPc

This is a normal constituent of the cell membrane and mainly has an alpha-helical structure. This protein form cannot be separated. Normal prion protein is said to have an important function of cell–to–cell adhesion and communication in the brain. It binds to copper ions with great affinity

2. PrPres

This is an isoform of the normal PrPc which is resistant to proteinase K and is structurally misfolded. It can or cannot be infectious.

3. PrPSc

This is a structurally altered form of the normal PrPc which is always infectious and causes disease. It is a discovered component for the infectious prion particles. The exact structure of the protein is still not known but it has structurally more than normal beta pleated sheets which form amyloid fibers, which eventually accumulate forming plaques.

Function of Prion Proteins

The exact function of the prion proteins is still being researched but

experimental studies in mice have demonstrated that they play a role in

the regeneration of myelinated nerve fibers. In experiments performed on

mice,it was shown that breaking down ofprion proteins causes activation

of myelin repair and if they are not present then demyelination occurs in

those nerves.

In recent studies done from 2004 to 2005, it has been hypothesized that prion

proteins play a role in the maintenance of long term memory. In 2006, an

article from Biomedical research institute of Whitehead showed that prion

proteins are necessary for self-renewal of bone marrow. It stated that the

expression of these prion proteins on stem cells is necessary for self￾renewal.

Diseases Caused By Prions

• Sheep: Scrapie

• Cattle: Bovine spongiform encephalopathy (BSE), mad cow disease

• Mink: Transmissible mink encephalopathy (TME)

• White-tailed deer: Chronic wasting disease (CWD)

• Cat: Feline spongiform encephalopathy (FSE)

• Ayala, Oryx, greater Kudu: Exotic ungulate encephalopathy (EUE)

• Ostrich: a spongiform encephalopathy

• Humans: iatrogenic and variant Creutzfeldt-Jakob disease (CJD),

Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial

insomnia (FFI), Kuru, familial spongiform encephalopathy, multiple

system atrophy (MSA)these disease are sporadic, genetic or acquired

in origin. The abnormal prion proteins mimic as an infectious agent that

can cause transmission of disease from one organism to human or

inherited as a mutant.

Potential Treatments and Diagnosis

There are no definitive means of diagnosis and treatment till now but some

methods are being used. They are as follows:

• Antibodies against PrP have shown some promising effects.

Antibodies against PrP were used in prion-infected mice and they were

treated successfully under specific conditions.

• Gene silencing is another method still under trial in which genes

causing prion disease are stopped or turned off.

• Stem cell therapy is another proposed therapy for the treatment of

prion diseases. It can be used to make new brain cells against the

damaged brain cells.

• Astemizole is found to have an anti-prion activity that can cross blood￾brain barrier and inhibit the activity of prion.

-Lavanya N