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Discovery Reveals How Chronic Stress Causes Brain Damage

Daegu (KR), August 2019 — A new study shows how chronic stress causes autophagic death of adult hippocampal neural stem cells (NSCs). These findings, by a team of scientists at DGIST (Daegu Gyeongbuk Institute of Science and Technology), are expected to open up new strategies for combatting stress-associated neural diseases.

Chronic stress is infamous for its association with various mental diseases such as depression and schizophrenia. Stress can even raise the risk of neurodegenerative diseases, including Alzheimer's.

However, the exact mechanisms underlying damages of brain functions are not well known. While previous studies found that generation of new neurons is much less in stressed mice, apoptosis1, a well-known cell suicide pathway, was not found in the NSCs, leading to the conclusion that cell death is not related with loss of NSCs during stress. Thus, the cause of decline in adult neurogenesis2, which is generation of new neural cells in the adult brain — especially in hippocampus — has remained a mystery.

Now, for the first time, a team of researchers, led by Seong-Woon Yu, Ph.D., in DGIST’s Department of Brain and Cognitive Sciences, discovered how chronic stress causes autophagic death of adult hippocampal NSCs. Autophagy (“self-eating” in Greek) is a cellular process to protect cells from unfavorable conditions through digestion and recycling of inner cell materials; thereby cells can remove toxic or old intracellular components and get nutrients and metabolites for survival.

However, autophagy can turn into a self-destruction process under certain conditions, leading to autophagic cell death. Autophagic cell death is a form of cell death distinguished from apoptosis by the causative role of autophagy for cell demise.

Using the NSCs derived from rodents and genetically modified mice, the research team discovered that the death of hippocampal NSCs is prevented and normal brain functions are maintained without stress symptoms when Atg7, one of the major autophagic genes, is deleted.

The research team also further examined the mechanism controlling the autophagy induction of NSCs in more depth, proving that the SGK3 (serum/glucocorticoid regulated kinase3) gene is the trigger for autophagy initiation. Therefore, when SGK3 is removed, hippocampal NSCs do not undergo cell death and are spared from stress.

Professor Yu said, "It is clear from our study that cognitive defects and mood disorders brought about by stress is through autophagic death of adult hippocampal NSCs. With continuous research, we'll be able to take a step further toward the development of effective treatment of psychological disorders such as depression and anxiety. Furthermore, stress-related neurodegenerative diseases including dementia could also benefit from our study.

“We hope to be able to develop much faster and more effective mental disease treatments through joint research with the Chinese National Compound Library to develop SGK3 inhibitor together."

Induction of autophagosome formation by stress and protection of hippocampal neural stem cells from stress by the deletion of autophagy gene Atg7. Image courtesy of DGIST.


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