Prion of yeasts can help to understand the characteristics of the development of neurodegenerative diseases

Sometimes human and animal proteins lose their normal folding and form specific filariform aggregates, or fibrils, called amyloids. These structures can activate chain reaction, attaching to themselves new and new molecules with normal form of the same protein, changing its folding for the same as theirs. This enables amyloids to grow, multiply and spread in the organism, causing incurable diseases – amyloidosises, among which the most widespread by people are  Alzheimer and Parkinson.  Nowadays tens of millions of people all over the world suffer from them, and this number is quickly growing in the course of aging of humanity, that presents the significant challenge for the world’s healthcare. Besides this, some amyloids are able even to infect other people or animals, so they were called – prions, that means infectious proteins.  It is with them that the group of comparatively rare, although rather well-known diseases, such as  Creutzfeldt–Jakob disease, kuru, mad cow disease and scrapie of sheep is connected.

However, prions are harmful not for all living organisms. Thus, as far as yeast – single-celled microfungi – is concerned, prions don’t cause any significant damage to cell, and sometimes may be even useful,  increasing its resistibility to unfavorable environmental conditions.

Studying of prions and amyloids on living models is a long, laborious and even dangerous process, and that’s why it demands high level of laboratory protection. Yeasts’ prions don’t have such shortcomings and so they are a convenient model for scientists. Information, obtained with their help, can be used for elaboration of drugs against neurodegenerative diseases.

Scientists from the Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences analyzed a lot of works studying the characteristics of yeasts’ prions and made summary of their results. In it they tried to give the fullest picture of molecular construction of these proteins and the mechanisms of their cooperation with a cell.

Thus, in the article there is a thorough description of the mostly studied yeasts’ prion – Sup35, which participates in control of protein synthesis. If there accidently appears a mutation in the organism’s genome, that finishes the protein synthesis too soon, prion Sup35 enables to overcome this failure. For example, yeasts with gene mutation  ade-14 are not able to synthesize adenin because of interruption of this process in the certain place, correlating with mutation in the gene. That leads to accumulation of intermediate product – pigment that gives red coloring to yeast colonies. However, if there is a prion Sup35 in the cell, it helps to overcome mutation ade-14 and lead synthesis of adeine to the end. As a result colored product is not accumulated and the color of the colonies is changed for the white one or various shadows of pink, depending on prion’s “power”.

In the review authors clearly demonstrate the structure of prion Sup35 and protein, cooperating with it. Probably it was the first time that such picture was able to be presented with maintenance of all molecular proportions. It enables the scientists to demonstrate the unique ability of amyloids: very thick packing of protein molecules in the amyloid fibril. Thus, one protein molecule in the amyloid’s composition takes 11 times less space on the fibril’s length, than the molecule of actin in the muscle bundle. Therefore, it was possible to demonstrate in the picture only a small part of all molecules, cooperating with prion Sup35. Such a thick packing is to put restriction on cooperation of amyloid with other molecules, particularly with chaperone protein, which try to “struggle’ with prions, dissolving them.

Interestingly enough, this struggle usually gives the contrary result, helping prions to multiply. Interesting feature of yeast’s prions, as also of all amyloids, consists in that, if you elicit only one protein molecule from its thick composition, that the very thing the chaperone Hsp104 does, prion falls to two parts. By this, both new fragments remain able to “infect” normal proteins. This exactly how prion particles multiply. In respect to yeast this process is necessary to provide daughter cells with the same amount of prions in the course of division. In the human organism the division of prions and amyloids into smaller and more mobile fragments enables them to spread inside the organism more easily. There are also many facts that tell that they are more toxic.

Prion proteins of yeasts usually contain two parts. One of them, rather small, forms the amyloidal axis of prion . The other – answers for the function of the protein, and this function lessens or modifies, when normal protein transforms to prion. Many researches made clear, that when this functional area is situated at the very beginning or end of the protein, its transformation to prion form is more likely to occur.

But the authors of the review found out more significant phenomenon: if due to the mutation the synthesis of the protein finishes prematurely exactly after priongenic area, placing it on the end of the protein, the frequency of primary appearing of prion increases in 6000 times. This observation supports and detailizes one the most popular hypothesis on appearing of amyloids in the human organism as a result of somatic mutations. And the calculations show that the number of cells with such mutations that can become the center of appearing of amylodoisis in the organism of every human can be measured by millions.