Prion (protein)

The term prion is a Mot-valise, coming from English “ proteinaceous infectious particle ” (proteinic infectious particle). Let us request play a crucial role in the good (or the bad one) folding up of the Protéine S, which will make it possible to make or not them functional. In this direction, the “infectious” which was allotted to him in the beginning is not to take literally.

Normal and pathological proteins

The protein prion Prp-c present at the natural state and is implied in the normal functioning of the cell. Its functions, are not yet known precisely but they are suspected essential. Indeed, the Prp-c protein was present before the Spéciation, which means that all the mammals (including the man) are likely to develop diseases with request. The Prp-c protein is implied in the development of the nervous system at the embryo. In the adult, it is expressed primarily in the Cerveau and the spinal-cord (neurons and glie). It is implied in the processes of differentiation and adhesion of the cells. It would have also an antioxydant protective role and with respect to programmed cellular death (Apoptose). This protein would also have a role in the folding up of other proteins. According to the team of Dr. Scott (December 2006), the protein prion normal, studied in the rat, present of particular accumulations inside the cells of the pancreas specialized in the production of Insulin, and the rats predisposed with the diabetes present 3 times more producing insulin cells with protein clusters request. The protein rate let us request in the pancreas of a normal rat strongly changes in the one at three days following the administration of high sugar concentrations via blood. The protein prion could be implied in the diabetes of the type 1 or youthful, diseases characterized by an attack by the immune system of the cells producing insulin (in the pancreas).

The pathogenic prion is a transferred protein prion Prp-c (one is unaware of the cause of this change) who causes the diseases with request (Maladie of the mad cow, or bovine spongiform encephalopathy, Maladie of Creutzfeldt-Jakob, Chronical Wasting Disease or disease of the insane stag). During the infection, the agent prion, disease-causing agent responsible for the infection, penetrate the neuron, where for reasons and by a mechanism still badly included/understood it " reproduit" exponentially, by deforming the healthy proteins prion out of transferred proteins prion going until causing the explosion of the nervous cell literally.

The abnormal protein prion or Prp-Sc, which is responsible for the disease, results from a modification of its three-dimensional structure, whose origin is vague. This form confers atypical physicochemical properties to him which result in a very great resistance to the means of usual disinfection and sterilization (heat, chemicals, enzymes, etc). It acquires capacities of car-aggregation and can thus form deposits in particular in the Cerveau, causing neuronal death.

The nature of “the infectious agent prion” is still discussed and prone to assumptions. No nucleic acid (ADN/ARN) could be specifically associated with the infectivity, like could it be the abnormal protein prion. One speaks about NonConventional Transmissible Agent (ATNC). The theory of the prion or infectious protein, developed by the mad cow, currently is best supported. One can also quote, the theories of a conventional virus (too much small to be currently detected), virino (small ARN/ADN masked by proteins prion), or molecule car-chaperonne (able to modify its own conformation). The diseases with let us request are transmissible from one individual to another and to a certain extent from one species to another.

Diseases

Disorders due to its presence

The diseases with let us request cause a degeneration of the central nervous system which is always fatal.

the role of let us request is established in certain animal affections such as the bovine spongiform Encéphalopathie (ESB or disease of the mad cow ), the trembling of the sheep and the goat , or the disease of the chronic deterioration of the deer tribe.

At the man, it is responsible for the Maladie of Creutzfeldt-Jakob which is characterized by a dementia praecox leading to the death. The common form is sporadic, generally reaching the old subject. It can be seldom family, with in this case an implication of gene of the protein prion. It can be also transmitted by contaminated fabric inoculation (extracted from Hypophyse employed before in the treatment by the growth hormone, Clerc's Offices of cornea and dura mater, electrodes contaminated).

In March 1996, appeared a clinical form at the young subject (< 30ans), called new varying disease of Creutzfeld-Jakob , whose bond with the ESB was proven then. The transmission would be due probably to the bovine meat ingestion contaminated by the ESB. The prion is also the cause of other human diseases: kuru today disappeared (concerning a tribe of Papous of New Guinea which was the 1st human spongiform encephalopathy of which the transmissibility with the monkey was shown), the disease of Gertsmann-Sträussler-Scheinker and the fatal family insomnia .

It should be noted that there exist other neurological diseases comprising of accumulations of the abnormal proteins, most famous being the Maladie of Alzheimer and the Parkinson's disease. The responsibility for a prion however was not shown in these cases, although it can coexist.

Disorders due to the absence of let us request

The available data come from experimentation of transgenèse on mice/hamsters with which one withdrew gene of the protein prion and thus does not have any more this protein, or which one can stop at will the production of protein prion. This work makes it possible to elucidate little by little the functions of the normal protein prion. Certain mice deprived of protein prion by Knocked-out of the gene prnp coding this protein, are viable and fertile, without apparent Phénotype. Others develop a massive neuronal death with the level of the Cervelet. This death is due to another protein, Paralogue with the healthy protein prion Prp-c, called Doppel (Dpl).

It is more of the experimental models than true request since it misses in these cases the concept of “infection”. “Let us request” yeast are not proteins prion such as in the animals, but are actually proteins (often of thermal shock) which miment the behavior of these abnormal proteins prion: under certain conditions of stress, they change conformation and accumulate, disturbing the cellular operation of yeast.

It was noted by experiments of centrifugation of DNA that without some request, the brewers' yeasts cannot reproduce correctly.

Mechanisms

When the machinery and the components necessary (ARN-polymerase, Ribosome, etc) are present, it is possible to manufacture proteins starting from the DNA in accordance with the program which it contains. However, with identical composition, a protein can have more than one way of folding up , that is to say different conformations.

It was noted that the abnormal protein prion supports a type of abnormal folding up. However on good or the bad way in which is folded up a protein depends its functionality. For this reason and according to the Theory of Prusiner, the DNA necessarily does not have with him only all information as opposed to what to produce the material which the organization needs , one believed a long time. The role of protein with normal conformation remains to be specified.

The most powerful computer of the world (in 2004), Blue obstructs, was ordered by the Lawrence Livermore Laboratory to study in a systematic way, by simulation, foldings up of involved proteins and in the absence of let us request.

The yeast of Bière could be an interesting experimental model: some of its proteins have properties of “contagion of form” which evoke those of the request , even if the assimilation with these last is discussed.

Detection

The diagnosis of the disease is made in a current way in the died animal, on neurological taking away of fabrics, in which the abnormal protein prion concentration is most important at the sick individual. The tests are based on the analysis of the residues of protein after digestion to the protease and also on the detection of the abnormal protein prion using specific antibodies. Two methods are used in order to locate protein in fabrics: the western-blot which allows the analysis of the size of the residues after proteolytic digestion and immuno-histo-chemistry (or immunohistochimy) which highlights the specific complex antibody abnormal protein prion.

By gaining of sensitivity (detection of a low number of particles), one hopes to be able to make, in the future, a diagnosis by a simple blood test on an alive subject.

One can also seek the prion in other bodies, in particular in the muscles.

Treatments

Preventive

It rests on:

the detection and the elimination of the carrying animals;
the detection of the subjects at the risk having to lead to increased precautions when they require an exploration.

A vaccine is difficult to find because of presence of request “normal” in the organization. The Swiss researchers thus modified genes of the mice so that their lymphocytes B manufacture antibodies which will be able to differentiate a pathogenic prion from a normal prion. Nevertheless, there does not exist to date Vaccin, nor of serum having shown an effectiveness.

Curative

Several molecules were tested and seem to have shown a deceleration of the progression of the disease. Among them one can quote the Quinacrine , a anti-paludic , and the polysulfate of Pentosan.

One of the main obstacles to an effective cure is that they are diseases of the brain, separated of blood circulation by a hemato-encephalic Barrière preventing the passage of the majority of the molecules.

Eradication

The prion is a solid protein, destroyed primarily by the high temperatures (attention: some resist 100 °C). To date, no decontaminating substance current showed absolute effectiveness (Antiseptique, Bleach…). Not having a Metabolism, it is hardly vulnerable to the irradiations used usually with an aim of sterilization.

Others

Research on the prion was the two object Nobel Prize of medicine:

D. Carleton Gajdusek in 1976 for its work on the kuru ;
Stanley B. Prusiner in 1997 for its theory on the prion, infectious protein.

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