Protective protein sirtuin-6 will reveal the causes of aging and neurodegenerative diseases

Russian scientists, together with foreign colleagues, found out that the nuclear protein sirtuin-6 is the central regulator of the activity of cellular “energy stations” – mitochondria in the brain. It is involved in the protection of DNA from damage, the metabolism of fats and glucose, and in many other important processes, in addition, without it, the energy supply of the cell is disrupted. Approximately the same thing happens with neurons in aging and neurodegenerative diseases, and therefore the results of the study will help develop new approaches to the prevention and treatment of these diseases. The results of the work, supported by a grant from the Russian Science Foundation (RSF), were published in the journal Cell Death and Disease.

Aging at the cellular level is accompanied by genome instability due to the “wear and tear” of damaged DNA repair systems. As a result, the work of proteins encoded in DNA, which generally control the vital activity of the cell, is disrupted. The deterioration of the functions of its “energy stations” – mitochondria – is very critical and most noticeable: a cell, like a phone with a dead battery, can only minimally maintain its performance or completely stop it and die. This happens with aging, and due to degenerative pathologies, such as Alzheimer’s and Parkinson’s diseases, which means that the mechanisms for these conditions are similar.

Researchers at the Skolkovo Institute of Science and Technology (Moscow), together with foreign colleagues, focused on studying the function of the mammalian nuclear protein sirtuin-6, which can split off a small group of atoms from DNA “packers” and thereby control its folding and unfolding, and hence the activity of genes. . It ensures the integrity of the hereditary material and the end sections of chromosomes – telomeres (one of the hypotheses of aging is just related to their shortening), regulates cell metabolism, and also plays an important role in protecting against diseases associated with aging and destruction of neurons. The authors decided to find out exactly how this protein affects the work of mitochondria in the brain of mice.

The participants in the experiment were mice with a breakdown of the sirtuin-6 gene – that is, they had less than the norm for this protein. Biologists have isolated RNA from the brains of animals and deciphered its sequence to understand exactly which genes work in neurons. The scientists also analyzed the amount of substances associated with the activity of mitochondria.

The results of the work showed that the lack of sirtuin-6 leads to pathological changes. So, almost 3,000 genes were affected, and those associated with mitochondria were especially affected. This was also confirmed by disturbances in the metabolism of the latter: there were fewer substances participating in oxidative phosphorylation in the samples, as a result of which the energy of nutrients is stored in the form of the basic “energy currency” of living organisms – adenosine triphosphate (ATP). Cell respiration also became less efficient. The authors noted a direct link between the lack of sirtuin-6 and the death of mitochondria – with a decrease in protein levels by 20%, there were approximately the same number of these organelles in the brain cells of mice. All these dramatic consequences are explained by the richness of sirtuin-6 contacts with other proteins.

“Our results clearly demonstrate that a decrease in the level of sirtuin-6 in the brain of the elderly may be almost the main cause of age-related neurodegenerative diseases. Now we have to look into the details: why this is happening. Now we are trying to test the hypothesis that everything can be tied to DNA packaging, because sirtuin-6 splits off a group of atoms from DNA “packers” and thereby controls its folding and unfolding. The published results are the first step in our large-scale study, supported by a grant from the Russian Science Foundation, which is devoted to the study of DNA packaging in normal and in various pathologies of the human brain. We have already received our experimental data on DNA packaging in the human brain and are now actively analyzing them,” says Ekaterina Khrameyeva, head of the project supported by the RSF grant.