Prions: Characteristics, Structure, Functions, Diseases

The prions are proteins without nucleic acid genome or which act as infectious agents. The term “prion” means proteinaceous infectious particle (from English Proteinaceous Infectious Particles), and was coined by the neurologist and Nobel Prize winner, Stanley B. Prusiner.

In 1982, Prusiner and his colleagues identified an infectious protein particle while studying the causes of Creutzfeldt-Jakob diseases (in humans) and bovine spongiform encephalopathy.

These rare infectious agents are found in the membrane of normal cells, only as misfolded proteins and / or with an abnormal three-dimensional structure. These proteins are responsible for multiple degenerative diseases and very high mortality that they affect neural tissues and brain structure.

They are also called prion diseases. Among the most important that affect humans are kuru, Gerstmann-Sträussler-Scheinker disease, Creutzfeldt-Jakob syndrome and fatal familial insomnia.

General characteristics

Prions are protein structures present in cell membranes. These proteins have an altered shape or conformation [PrP (Sc)].

With regard to its multiplication, it is achieved through the conversion of forms, as in the case of scrapie disease. In this disease, prions recruit PrP (C) (prion proteins of unaltered conformation) to stimulate conversion to the PrP (Sc) isoform.

This generates a chain reaction that spreads the infectious material and therefore allows the irrigation of the disease. How this conversion process occurs is still unknown.

These unusual proteins capable of propagation do not have nucleic acids. Proof of this is that they are resistant to X-rays and ultraviolet radiation. These agents easily break down nucleic acids.

Prion proteins, of which prions (PrP) are composed, are found throughout the body, not only in humans but in other healthy vertebrates . These proteins are generally resistant to proteases (enzymes that catalyze proteins).

Very little is known about the usefulness of the PrP (C) prion proteins, the normal form of the non-infectious protein in the human body.

However, some researchers have succeeded in showing that, in mice, these proteins activate myelin repair in cells of the peripheral nervous system . The absence of these has also been shown to cause demyelination of such nerve cells.

Structures

The knowledge that is had about the structure of prions resides mainly in the investigations carried out in the bacterium Escherichia coli .

Studies have shown that the polypeptides in the chain PrP (C) (normal) and PrP (Sc) (infectious) are identical in the composition of amino acids, but differ in their 3D conformation and their folding.

PrP (C)

These non-infectious prions have 209 amino acids in humans. They have a disulfide bond. Its structure is alpha-helical, which means it has spiral-shaped amino acids (alpha helices) and few flat strands of amino acids (beta sheets).

This protein cannot be separated by centrifugation, which implies that it is not sedimentable. It is easily digested by the broad spectrum serine protease called proteinase K.

PrP (Sc)

It is an infectious protein that transforms PrP (C) into infectious PrP (Sc) isoforms with an abnormal configuration or shape.

Very little is known about its 3D structure, however it is known that it has few helical shapes and more flat strands or beta sheets. The shift to the isoform is what is known as the pivotal event of prion diseases.

Features

Cellular prion proteins [Prp (C)] are located on the cell surface of a wide variety of organs and tissues. Very little is known about the physiological functions of prions in the body. Even so, experiments done in mice indicate possible functions, such as:

With metabotropic glutamate receptors

It has been shown that PrP (C) act with glutamate receptors (ionotropic and metabotropic). PrP (C) participates as a receptor for synaptotoxic oligomers of the cell surface Aβ peptide.

In embryonic development

In mice of the Murinae family, the prion proteins PrP (C) have been found to be expressed within a few days after implantation, in embryonic development.

This indicates that they play a role during the development of these small mammals. Role that according to the researchers is related to the regulation of neuritogenesis (production of axons and dendrites of neurons).

TThey also act on axonal growth. These prion proteins are even involved in the development of the cerebellar circuit. Because of this, it is believed that the absence of these PrP (C) prions leads to a delay in the motor development of rodents.

Neuroprotective

In studies on the overexpression of PrP (C) by gene orientation, it was found that the absence of these prions causes problems with the blood supply to some places in the brain (acute cerebral ischemia).

This means that prion proteins function as neuroprotectors. Additionally, it has been shown that PrP (C) overexpression can reduce or improve injuries caused by ischemia.

Peripheral nervous system

Recently the physiological role of Prp (C) in the maintenance of peripheral myelin was discovered.

During a laboratory study it was discovered that in the absence of the prion protein, laboratory mice developed deficiencies in the nerves that carry information from the brain and spinal cord, in what is called a peripheral neuropathy.

Cell death

There are some proteins that are similar to prions, and these are located in other parts of the body than the brain.

The functions of such proteins is to initiate, regulate and / or control cell death, when the organism is being attacked (by virons for example), thus preventing the spread of the pathogen.

This peculiar function of these proteins makes researchers think about the possible importance of non-infectious prions in the fight against pathogens.

Long term memory

A study conducted at the Stowers Institute in Missouri, USA, showed that PrP prions may play a role in maintaining long-term memory .

The study revealed that certain prion proteins can be controlled to work in maintaining the physiological functions of long-term memory .

Stem cell renewal

An investigation on prion proteins that are expressed in blood tissue stem cells, revealed that all these stem cells (hematopoietic) express prion proteins in their cell membrane. So it is believed that they participate in the complex and very important process of cell renewal.

Diseases caused by prions

Pathologies of prion origin are recognized as progressive degenerative brain disorders. They can attack cattle, deer, caribou, sheep, and even humans.

These diseases are caused by an alteration in the structure of the PrP (C) proteins and whose specific functions are still uncertain today. Prion pathologies can arise without a known cause. They can have an inherited genetic origin and can also be transmitted in an infectious-contagious way.

Prions cause familial, sporadic, and contagious diseases. Familial prion diseases are those that are heritable. Sporadic pathologies are the most common and occur without known causes.

Contagious diseases are considered rare, they are transmitted by person to person, animal to animal, person to animal and vice versa. The causes are multiple and range from consumption of contaminated meat, cannibalism, transfusions, to handling of contaminated surgical equipment.

The most common prion diseases are:

Creutzfeldt-Jakob disease (CJD)

Considered the most common prion disease among human beings, it is a cosmopolitan disease, that is, it has a worldwide distribution. It can be hereditary (familial), sporadic, or infectious.

Patients present with symptoms such as dementia, jerks or sudden involuntary movements, and central nervous system deficiencies .

Depending on the treatment and form of the disease, death can occur between 4 months to 2 years after the acquisition of the disease. The diagnosis is difficult to make, it is usually made post- mortem, during the autopsy.

Gerstmann-Sträussler-Scheinker disease

It is a disease caused by prions in an inheritable or autosomal dominant infectious brain process. The disease manifests itself in people aged 40 to 60 years.

These people manifest problems to articulate words (dysarthria), jerks or sudden involuntary movements, aggressiveness being frequent.

They present with cerebellar degeneration accompanied by an unsteady gait. It is also possible to observe hyporeflexia, deafness, gaze paralysis, dementia, among other symptoms. Life expectancy is about 5 years or a little longer.

Prionopathy with variable sensitivity to protease

It is a very rare disease, to the point that its occurrence range is 2 to 3 cases per 100 million inhabitants. The pathology is similar to Gerstmann-Sträussler-Scheinker disease.

The clinical manifestations of the protein indicate low resistance to proteases, some are more and others less sensitive to these enzymes.

The symptoms that patients present are: problems with speech and cognitive impairment, loss of neurons in the area where the brain controls movements and performs muscle coordination.

The disease is common in elderly patients (70 years) and the estimated life span once infected is approximately 20 months.

Fatal insomnia

It is a hereditary or familial disease, it can also occur sporadically. The disease is known to be due to a hereditary or autosomal dominant mutation.

Patients present symptoms such as cumulative problems sleeping and maintaining sleep, dementia, cognitive impairment, even problems of hypertension, tachycardia, hyperhidrosis, and others.

The age it affects is quite wide, ranging between 23 and 73 years, however the average age is 40 years. The life span once infected is just over 6 years.

Kuru

This prion disease has been detected only in the inhabitants of Papua New Guinea. It is a disease related to cannibalism and the cultural tradition of the rite of mourning the dead, where these people eat brain or human flesh.

People who carry the disease usually have uncontrollable and involuntary movements in different parts of the body.

They present tremors, loss of control of movements and loss of muscular coordination. Life expectancy in infected people is two years.

Diseases in animals

Among the pathologies produced by prions in animals is bovine spongiform encephalopathy. This disease caused havoc in Europe, in public health, that of animals and in the economy of the affected countries.

Other diseases in animals include scrapie, transmissible mink encephalopathy, chronic wasting disease (in deer), and feline spongiform encephalopathy.

These diseases, like those presented in humans, lack an effective treatment, so prevention is essential especially after infections in humans that have occurred as a result of the consumption of meat from infected cows.

Treatments

To date there is no known cure for prion diseases. Treatment is symptomatic. Patients are advised to plan for palliative care and genetic testing and counseling for family members is recommended.

A wide variety of medications have been tested in patients with prion diseases, such as antivirals, antitumors, drugs for diseases such as Parkinson’s, treatments for immunosuppression, antibiotics, antifungals, even antidepressants.

However, there is currently no evidence that indicates that some of these reduce symptoms or improve survival of patients.

Prevention

Prions are resistant to a variety of physical and chemical changes. However, different techniques are employed to avoid contamination of patients with contaminated surgical instruments.

Among the most used techniques is to sterilize the equipment in an autoclave at 132 ° C for one hour and then immerse the instruments in sodium hydroxide for at least one more hour.

On the other hand, the world health organization (WHO) has developed measures to prevent the spread of prion diseases. This organization establishes norms for the handling of prohibited or potentially risky tissues such as: eyes, brain, intestine, tonsils and spinal cord.

References

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