A Korean research team has identified a key gene that prevents stressed brain cells from breaking down and dying on their own. Experts say the finding opens the door to a new class of psychiatric treatments that work differently from existing antidepressants.
According to the scientific community on Tuesday, a research team led by Professor Yoo Sung-woon of the Department of Brain Sciences at the Daegu Gyeongbuk Institute of Science and Technology (DGIST) has demonstrated for the first time that the p53 gene, widely known as the "death gene," conversely suppresses neuronal death in the brain.
Chronic stress is known to increase the risk of depression and anxiety disorders, as well as degenerative brain diseases such as dementia. In an earlier study, the team was the first to reveal that chronic stress induces "autophagic cell death" in neural stem cells of the hippocampus, the brain region responsible for learning and memory.
In the latest study, the team further clarified the precise mechanism that regulates this cell death process, newly identifying the p53 gene as the key brake controlling cell death.
The p53 gene is typically known as a representative cell death gene that suppresses cancer development by inducing damaged cells to die. However, the study found that in hippocampal neural stem cells, p53 acts as a "survival factor" that prevents cell death by suppressing the activity of a protein complex that promotes autophagy. In other words, p53 does not always act to eliminate cells but can also play the opposite role.
In experiments, mice with p53 removed from their neural stem cells showed significantly worsened memory decline and depressive and anxiety-related behaviors when exposed to chronic stress. Inside the cells, LC3, an autophagy-related protein, bound to the defensive factor p53 and broke down p53 itself, ultimately causing autophagy to proceed excessively and rapidly killing the neural stem cells.
The team also tested whether low-dose administration of RITA, an existing anticancer drug candidate, to mice could reduce depression and anxiety symptoms by preventing p53 destruction. The results showed that RITA interfered with the binding of LC3 and p53, preventing p53 from being degraded, and suppressing neural stem cell death even under chronic stress conditions. Cognitive decline and depressive and anxious behaviors in the mice were also significantly improved.
The team explained that the study presents a new treatment strategy distinct from existing antidepressants. Current antidepressants have mainly focused on regulating neurotransmitters such as serotonin. This study demonstrated the potential to treat stress-related brain diseases by protecting the neural stem cells themselves.
"We have proven for the first time that p53, known as the 'death gene,' conversely acts as a defensive shield that saves cells from stress in hippocampal neural stem cells," Professor Yoo of DGIST said. "A strategy that suppresses p53 degradation could lead to the development of psychiatric treatments based on a completely new concept that differs entirely from existing antidepressants."
The findings were published in Autophagy, an international academic journal in the field of autophagy, and the team has completed patent registrations in Korea and the United States related to RITA's antidepressant effects.
