Damage to the genetic material of nerve cells during brain development can trigger functional deterioration if the problem persists, as indicated by studies from Kyoto University and other institutions. This discovery sheds light on the mechanisms behind several neurological conditions.
Professor Kengaku, together with his collaborators from Kyoto University, revealed that the DNA of neurons suffers damage during the first phases of brain formation, in the city of Kyoto.
A team of researchers from Kyoto University and other entities confirmed, through experiments on rats, that the DNA of nerve cells is compromised while the brain is forming. This injury occurs when neurons, originating from stem cells, cross restricted spaces in the tissues, applying forces capable of drastically modifying the shape of their nuclei.
Most injuries recover naturally. However, when damage persists, it can result in nerve dysfunction and the manifestation of illnesses. The conclusions of this research were published in a prestigious British scientific journal, Nature magazine. The importance of this discovery lies in providing a deeper understanding of the cellular events that can ultimately lead to complex neurological disorders.
The cerebral cortex, the outermost layer, houses billions of neurons. These nerve cells, which arise from stem cells in deeper regions, migrate through dense tissue to reach the cortex. Although it was suspected that forces were applied in this path, there were few cases in which this phenomenon was actually observed in living organisms, which makes the methodology of this research a notable advance in neuroscience.
Professor Mineko Kengaku and her team at Kyoto University followed the journey of nerve cells in mice during the period of cerebral cortex development. They found that the shape of the nucleus changed significantly and the double helix structure of the DNA inside it broke when the cells moved through more compact tissues.
It is established knowledge that DNA double-strand breaks can cause cell death or the development of cancer. However, in this study, after completion of migration and formation of the cerebral cortex, the double-strand breaks disappeared, and the mouse brains followed normal development.
To further the investigation, experiments were carried out that artificially simulated narrow passages in the brain. Nerve cells and cancer cells were subjected to these passages, which were smaller than the diameter of the nucleus. It is known that cancer cells also suffer DNA double-strand breaks under compression in tight spaces. The difference observed was that, in cancer cells, the nuclear membrane ruptured, while that of nerve cells remained intact.
In cancer cells, disruption of the nuclear membrane allows DNA to come into contact with degrading enzymes within the cell, causing breaks. Analysis of the neurons revealed that topoisomerase, an enzyme that normally acts to undo kinks in DNA within the nucleus, was also inducing breaks due to mechanical stress. These breaks, however, were concentrated in areas not essential for gene function and were repaired quickly.
When mice were genetically modified to have a deficiency in the ability to repair DNA, their nerve cells at first appeared to develop normally. However, subsequently, the activation of inflammatory cells and a decrease in the expression of genes crucial for neural function were observed. With advancing age, the cerebellar function of these animals began to decline, and disturbances such as changes in gait were noted.
Professor Kengaku expresses his future research goal: “I want to clearly understand the significance of DNA damage in the brain genome.”