Researchers discovered that chronic stress causes autophagic death of adult hippocampal neural stem cells (NSCs)


DGIST announced on July 2 that Professor Seong-Woon Yu’s team in the Department of Brain and Cognitive Sciences discovered that chronic stress causes autophagic death of adult hippocampal neural stem cells (NSCs).

These findings 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 that have become very serious social problems.

Stress can even raise the risk of neurodegenerative diseases, such as Alzheimer’s disease.

However, the exact mechanisms underlying damage of brain functions have not been well known yet.

While the previous animal studies found that generation of new neurons is much less in stressed mice, apoptosis, a well-known cell suicide pathway was not found in NSCs, leading to a conclusion that cell death is not related to loss of NSCs during stress.

Thus, the cause of decline in adult neurogenesis, which is generation of new neural cells in the adult brain, especially in hippocampus, has remained .

Professor Yu’s team discovered for the first time that 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, whereby 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 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.

Scientists at DGIST discovered how chronic stress causes brain damage
Preservation of hippocampal neural stem cells from chronic stress by SGK3 knockdown. Credit: DGIST

The research team also further examined the mechanism controlling the autophagy induction of NSCs in more depth, proving that SGK3 (serum/glucocorticoid regulated kinase) gene is the trigger for autophagy initiation.

Therefore, when SGK3 gene is removed, hippocampal NSCs do not undergo cell death and are spared from stress.

Professor Yu in the Department of Brain and Cognitive Sciences said, “It is clear from our study that cognitive defects and mood disorders brought about by stress are 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 be also benefited 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.”

Macroautophagy/autophagy is a lysosome-dependent catabolic process characterized by increased formation of double-membraned autophagosomes for sequestration of cytoplasmic components.

Autophagy is essential for normal development and physiology, and is generally considered as a cell survival mechanism that supplies nutrients and ensures turnover of obsolete cellular constituents [1Mizushima N, Levine B, Cuervo AN, et al. 

Autophagy fights disease through cellular self-digestion. Nature. 2008;451(7182):1069–1075.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

However, accumulating evidence suggests that autophagy may cause or contribute to cell death under certain conditions [2Tsujimoto Y, Shimizu S. Another way to die: autophagic programmed cell death. Cell Death Differ. 2005;12(Suppl 2):1528–1534.[Crossref][PubMed], , [Google Scholar]].

Recent progress in the field of cell death indicates the importance of the modes of programmed cell death (PCD) other than apoptosis, such as autophagic cell death (ACD) or necroptosis in human physiology and diseases [3Tait SW, Ichim G, Green DR. Die another way–non-apoptotic mechanisms of cell death. J Cell Sci. 2014;127(Pt 10):2135–2144.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

The best demonstration of the role of ACD in physiological cell death was presented in the model organism Drosophila, where ACD acts as a cell death mechanism independent of apoptosis in the removal of the larval midgut during development [4Denton D, Shravage B, Simin R, et al. Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Curr Biol. 2009;19(20):1741–1746.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

In mammals, authentic cases of ACD are rare.

We have previously reported that adult hippocampal neural stem (HCN) cells isolated from adult rats undergo ACD following insulin withdrawal despite their intact apoptotic capabilities [5Yu S-W, Baek S-H, Brennan RT, et al. Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells. 2008;26(10):2602–2610.[Crossref][PubMed][Web of Science ®], , [Google Scholar]8Ha S, Jeong S-H, Yi K, et al. Phosphorylation of p62 by AMP-activated protein kinase mediates autophagic cell death in adult hippocampal neural stem cells. J Biol Chem. 2017;292(33):13795–13808.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

Autophagy flux is increased in insulin-deprived HCN cells without signs of apoptosis or necrosis, and genetic inactivation of autophagy protects HCN cells from cell death induced by insulin withdrawal. Hence, insulin-deprived HCN cells have been considered to be a genuine model of ACD that meets all criteria of ACD proposed by Shen and Codogno [9Shen HM, Codogno P. Autophagic cell death: loch Ness monster or endangered species?. Autophagy. 2011;7(5):457–465.[Taylor & Francis Online][Web of Science ®], , [Google Scholar]].

However, our previous studies have been restricted to in vitro cell cultures, and the physiological importance of ACD in vivo and relevant molecular mechanisms in mammals still remain to be demonstrated.

Hippocampus is one of the regions of the mammalian brain where neural stem cells (NSCs) reside and sustain the generation of new neurons throughout adulthood.

Adult hippocampal neurogenesis is implicated in learning and memory, and mood regulation [10Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132(4):645–660.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

However, adult hippocampal neurogenesis is highly susceptible to stress and the major stress hormone, glucocorticoid (GC) [11Gould E, Cameron HA, Daniels DC, et al. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J Neurosci. 1992;12(9):3642–3650.[Crossref][PubMed][Web of Science ®], , [Google Scholar]13Egeland M, Zunszain PA, Pariante CM. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci. 2015;16(4):189–200.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

Therefore, alteration in adult hippocampal neurogenesis is intimately involved in stress-induced psychological disorders, such as anxiety, depression, post-traumatic stress disorder, and panic disorder [14Kheirbek MA, Klemenhagen KC, Sahay A, et al. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci. 2012;15(12):1613–1620.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

It is unclear whether PCD affects the balance between the survival and death of adult NSCs and thus mediates the suppressive effects of stress on adult neurogenesis.

Previous studies suggested that apoptosis is not involved in stress-induced suppression of adult neurogenesis, as evidenced by the lack of DNA fragmentation or caspase-3 activation as an indicator of cell death [15Lagace DC, Donovan MH, DeCarolis NA, et al. 

Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proc Natl Acad Sci U S A. 2010;107(9):4436–4441.[Crossref][PubMed][Web of Science ®], , [Google Scholar],16Koo JW, Russo SJ, Ferguson D, et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A. 2010;107(6):2669–2674.[Crossref][PubMed][Web of Science ®], , [Google Scholar]].

Here, we report that chronic stress induces ACD of adult hippocampal NSCs, thereby suppressing adult hippocampal neurogenesis.

Our study demonstrates the genuine in vivo case of ACD in a mammalian system. Our results also shed new light on the pathological mechanisms underlying detrimental effects of chronic stress on cognitive performance and may provide potential clues for the design of treatment of chronic stress-related neurological disorders.

More information: Seonghee Jung et al, Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits, Autophagy (2019). DOI: 10.1080/15548627.2019.1630222

Provided by DGIST (Daegu Gyeongbuk Institute of Science and Technology)


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