DNA damage is responsible for memory and age-related neurodegeneration
Researchers at the Massachusetts Institute of Technology, working under the guidance of Professor Li Huei Tsai, have found that the process by which a person remembers new information also leads to age-related neurodegeneration.
According to the authors, every time a person remembers something, the neurons of his brain physiologically damage their DNA. Such damage, which is subject to immediate repair, ensures the expression of early response genes, which leads to the launch of a transcription program that supports learning and memorization, as well as many other mechanisms. However, as we age, the effectiveness of DNA repair mechanisms decreases, which leads to the accumulation of damage and the extinction of mental abilities.
When conducting an earlier study on mice devoted to the study of Alzheimer's disease, the authors found that even in the pre-symptomatic phase of the disease, the DNA of hippocampal neurons has many similar damages, namely double-stranded breaks.
To find out the causes of these lesions and the genes affected, the researchers exposed neurons to a toxic compound that induces double-stranded DNA breaks. After that, RNA was isolated from the treated cells for sequencing.
Subsequent processing of the obtained data revealed 700 genes damaged as a result of such exposure, the expression of most of which was expected to be reduced. However, oddly enough, it turned out that 12 genes known as genes for rapid response to neural stimulation, such as new sensory sensations, showed an increased level of expression in response to double-stranded DNA damage.
In order to find out whether such breaks appear naturally in the process of neural stimulation, the researchers treated neurons with a compound that causes the strengthening of synapses due to mechanisms similar to those triggered when receiving a new experience. Indeed, it turned out that such processing not only rapidly increases the expression of rapid response genes, but also leads to the appearance of double-stranded DNA breaks. Further experiments have shown that the topoisomerase-II-beta enzyme is responsible for the appearance of these breaks.
To get an answer to the question why early response genes need such an ambiguous expression mechanism, they studied the DNA regions adjacent to these genes using computer analysis methods. It turned out that these DNA fragments are enriched with a specific sequence of cytosine and thymine nucleotides, to which the CTCF protein (CCCTC-Binding factor) selectively binds. This "architectural" protein is known for its ability to form loops or bends of DNA.
In the case of early response genes, the loops formed by the CTCF protein act as a barrier preventing the interaction of different DNA fragments with each other – a critical stage in the mechanism of gene expression. Double DNA breaks help to overcome this barrier and increase the expression of these genes.
Thus, a paradox emerges, according to which the appearance of DNA damage considered potentially mutagenic and capable of causing cancer is a component of the physiological function of nerve cells.
Earlier studies have shown that the expression of genes involved in learning and memorization decreases as a person ages. Therefore, the authors plan to conduct further research in order to find out how age-related changes in the DNA damage repair system occur and how this disrupts the ability of neurons to cope with the need to form and immediately repair double-stranded DNA breaks. They also plan to find out whether in this case it is possible to increase the efficiency of damage repair with the help of certain chemical compounds.
Article by Li-Huei Tsai et al. Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes published in the journal Cell.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on MIT materials:
DNA breakage underlies both learning, age-related damage.
08.06.2015