Frail and stupid
Chemists have uncovered the biochemical mechanism of learning disabilities
Employees of the Faculty of Chemistry and the Institute of Functional Genomics of Moscow State University, as well as Skoltech, together with colleagues from Stockholm University (Sweden), have established a mechanism for assembling molecular machines that create proteins of cellular "batteries" — mitochondria. Mice with a violation of this mechanism turned out to be weak and did not respond to training at all. The scientists' article was published in Nature (Itoh et al., Mechanism of mitoribosomal small subunit biogenesis and preinitiation).
There are small energy factories in human cells — mitochondria. Once they were formed from bacteria that were absorbed by eukaryotes a long time ago. At the same time, two independent gene expression devices have been preserved in our body. Expression is a process in which hereditary information from DNA is converted into RNA and then into protein.
"One of the processes works in the nucleus and cytoplasm and was inherited from archaea, albeit in a highly modified form," says one of the co—authors of the work, Professor of the Department of Chemistry of Natural Compounds of the Faculty of Chemistry and Director of the Institute of Functional Genomics of Moscow State University, Corresponding member of the Russian Academy of Sciences Peter Sergiev. — The other, independent, is realized in the mitochondria, and we got it from bacteria. Accordingly, we have two types of ribosomes in our body — and two protein synthesis devices. Ribosomes are assembled on the basis of ribosomal RNA by attaching various molecules to it."
Scientists know quite well how the ribosome is assembled in the nucleus and cytoplasm.
"We are investigating what is happening in the mitochondria, because it has not been studied well yet,— continues Professor Sergiev. — And two years ago we discovered two enzymes that modify ribosomal RNA and participate in the assembly of mitochondrial ribosomes. By analyzing the intermediate stages of the process, we determined at what stage these enzymes — methyltransferases — work, how they help the assembly and what goes wrong in the assembly."
Then the chemists of Moscow State University began cooperation with the group of Alexey Amunts from Stockholm University, which specializes in structural studies of mitochondrial ribosomes.
"During this collaboration, our employee Ivan Laptev brought to Stockholm genetically modified cell lines in which, in our opinion, the key methyltransferases were inactivated," says Peter Sergiev. —Stockholm colleagues isolated mitochondria containing unfinished ribosomes and determined their structure by visualizing the assembly process."
Structural analysis fully confirmed the result of scientists from Moscow State University, obtained on the basis of functional data. The deciphered mechanism turned out to have a serious application. Scientists from the Faculty of Chemistry and the Institute of Functional Genomics of Moscow State University with colleagues from Skoltech raised mice with inactivated enzymes and looked at what was wrong with them.
"It turned out that these mice are weak, unbearable and untrained," said Pyotr Sergiev. — We tried to train them in different ways. For example, one of the standard experiments is that an animal is put in a lighted box, from which there are several exits. All but one end in a dead end, and one leads to her home cage, where she is cozy and comfortable. A normal mouse, having found the right way out, remembers it and immediately runs to it the next time. But a mouse with inactivated enzymes cannot remember the right path and searches for it again and again." An article about this work was published in the International Journal of Molecular Sciences (Averina et al., Mitochondrial rRNA Methylation by Mettl15 Contributes to the Exercise and Learning Capability in Mice).
Since mitochondria act as "batteries" of cells, the disruption of their work due to the inactivity of enzymes led to the fact that they were "discharged". This especially affects the most energy—consuming processes - muscle contraction (as a result, animals turned out to be weaker than their healthy relatives) and all those brain functions that determine intellectual abilities, although externally mice look quite normal.
As the scientist noted, the details of the mechanism still require serious study, so there is a lot of fundamental research ahead.
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