Healthy prions protect the membranes of nerve fibers
Scientists have found out the functions of prion protein in a healthy nervous system
Copper newsAn international team of researchers has found out the functions of the unchanged prion protein PrPC in the mammalian nervous system, writes Nature (Healthy prions protect nerves).
It turned out that this protein, capable of transforming into an infectious agent, is necessary to maintain the integrity of the protective myelin sheaths of nerve fibers.
Prions (English proteinaceous infectious particles, protein infectious particles) are a special class of purely protein, nucleic acid–free, infectious agents that cause severe diseases of the central nervous system in humans and a number of higher animals (so-called slow infections).
One of the first prion proteins characterized was PrP (from the English prion-related protein or protease-resistant protein). It can exist in two conformations – "healthy", PrP C, which it has in normal cells (C – from the English cellular, "cellular"), and "pathological" – PrP Sc, actually prion. The designation “Sc” is derived from the English name of the analogue of mad cow disease, the long–known disease scrapie (from scrape - scratch), sheep scratching, the cause of which is also a prion infection.
The prion protein PrP is found in the membranes of nerve cells. In some cases, the normal PrP C protein can change its structure by "folding" the amino acid chain in an alternative way. As a rule, the prion state of a protein is characterized by the transition of alpha-helices of the protein into beta layers. Such a modified prion protein is called the prion proper (PrP Sc) and is capable of converting it into new prions upon contact with PrP C.
The accumulation of prions is accompanied by their aggregation, the formation of highly ordered fibrils (amyloids), which eventually leads to cell death. This is manifested by damage to the brain tissue, in which many small cavities are formed, because of which the brain becomes like a porous sponge. In this regard, diseases caused by prions are called spongiform encephalopathies. In humans, these are Kreuzfeld-Jakob disease and Kuru disease – slowly progressing fatal brain lesions.
Attempts to understand the function of the prion protein have been conducted over the past two decades. The first genetically engineered mice devoid of PrP were created back in 1991. Then the researchers did not notice any negative consequences of its absence – the knockout animals turned out to be immune to prion infections without violating any vital functions.
However, in 1999, Japanese researchers showed that the absence of normal prion protein in mice leads to damage to the myelin sheaths of peripheral nerves. An international team of scientists led by Adriano Aguzzi from Zurich University Hospital decided to subject these data to a thorough systematic analysis, for which four lines of mice devoid of the PrP C gene were bred.
It turned out that in such animals, regardless of the line, signs of myelin defects are observed as early as six weeks after birth. At the age of two months, the nerve fibers were significantly demyelinated, which is why the mice had increased sensitivity to pain.
When scientists injected genetically engineered mice with normal prion protein directly into the nerves, demyelination did not occur. Moreover, this happened only with the introduction of PrP C, which is subject to enzymatic cleavage in the body. At the same time, when researchers injected prion protein into Schwann cells located around nerves and synthesizing fresh myelin, it was not possible to prevent demyelination.
As explained by Aguzzi, since the myelin sheaths were intact at birth in mice deprived of PrP, scientists concluded that the prion protein is necessary not for the formation of myelin, but to maintain its integrity throughout life.
Judging by the need for enzymatic cleavage of PrP in nerves, the mechanism of its action, according to the researchers, is as follows: when the myelin sheaths of nerve fibers wear out, an enzyme system is triggered that destroys the prion protein. Its fragments enter the Schwann cells, giving them a signal to start restoring myelin.
According to preliminary data, the prion protein acts in a similar way in the central nervous system. If this is confirmed, we will have to radically reconsider the tactics of potential treatment of prion infections: currently, scientists are looking for ways to eliminate PrP as an infectious agent, but if it turns out that brain damage is caused by its absence due to pathological transformation, it will be necessary, on the contrary, to maintain the content of normal PrP in nerve fibers.
In addition, according to immunologist Claude Carnaud, who studies prions at the Pierre and Marie Curie University of Paris, some brain diseases that are considered inflammatory (for example, multiple sclerosis) may actually be associated with the absence of prion protein, which will require a revision of the tactics of treatment of these diseases.
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