08 April 2022

Protective mutation

The nontranslating part of the gene protects against neurodegenerative disease

Kirill Stasevich, Science and Life (nkj.ru )

With amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), motor neurons die, that is, those that make muscles move, tense up and relax. Neurodegenerative processes gradually capture more and more groups of nerve cells, so that a person eventually stops talking and moving his eyes, he has to be artificially fed and also artificially maintained breathing.

As with all such diseases, the causes of Lou Gehrig's disease are not completely clear until the end. However, it is known that it increases inflammation, which includes microglia cells — they perform immune functions in the brain. Microglia reacts to dying neurons, seeking to destroy the focus of the disease. But the inflammatory reaction, which is triggered by immune cells, only makes it worse. Instead of suppressing the disease, microglia enhances it.


Microglia (green) grown in the laboratory from stem cells of ALS patients; cell nuclei are shown in blue.

But the inflammation may be much weaker due to one of the mutations in the IL18RAP gene. It encodes a protein that is part of the structure of the interleukin 18 receptor (IL18). Interleukin 18 belongs to the family of signaling proteins by which immune cells communicate with each other. In order to communicate, the signal must catch a special receptor on the cell membrane, and there is also such a receptor for IL18. And when IL18 sits on it, it triggers a chain of molecular events that increase inflammation.

Staff The Weizmann Institute analyzed The DNA of more than 6 thousand patients with ALS and more than 70 thousand healthy people, and as a result, a mutation was found in the IL18RAP gene, which reduces the likelihood of amyotrophic lateral sclerosis by five times. If the disease still started despite the mutation, then the mutation will noticeably slow it down. Experiments with individual cells have shown that microglia with a mutation in the IL18RAP gene are less aggressive towards neurons that control movements — at least when both live in a laboratory cell culture.

At the same time, what is important, the mutation does not affect the structure of the protein itself. It is located in the so-called untranslated region of the matrix RNA. As you know, information from any gene is first copied into an RNA molecule — into matrix RNA, or mRNA. But only part of the gene — and part of the mRNA — encode the actual sequence of amino acids that make up the protein. There are non-coding or untranslated sequences on both sides of the encoding sequence. They are untranslated because they do not participate directly in translation, that is, in protein synthesis. But on the other hand, they participate in translation indirectly — these RNA sites affect the efficiency of protein synthesis in different ways. For example, the stability of RNA as a whole may depend on untranslated sites.

An article in Nature Neuroscience (Eitan et al., Whole-genome sequencing reveals that variations in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS) states that a mutation in the non—coding region of IL18RAP just reduced the stability of its RNA - it was destroyed faster in the cell, and, consequently, microglial cells turned out there are fewer working receptors for the inflammatory signal. Obviously, this is why microglia did less harm to neurons, did not enhance ALS, and therefore the brain could cope with the disease in the bud. Whether these new data can be used in medicine to slow down amyotrophic lateral sclerosis, further research will show.

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