Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits

Seonghee Jung; Seongwon Choe; Hanwoong Woo; Hyeonjeong Jeong; Hyun Kyu An; Hyewon Moon; Hye Young Ryu; Bo Kyoung Yeo; Ye Won Lee; Hyosun Choi; Ji Young Mun; Woong Sun; Han Kyoung Choe; Eun Kyoung Kim; Seong Woon Yu

doi:10.1080/15548627.2019.1630222

Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits

Seonghee Jung, Seongwon Choe, Hanwoong Woo, Hyeonjeong Jeong, Hyun Kyu An, Hyewon Moon, Hye Young Ryu, Bo Kyoung Yeo, Ye Won Lee, Hyosun Choi, Ji Young Mun, Woong Sun, Han Kyoung Choe, Eun Kyoung Kim, Seong Woon Yu

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

83 Citations (Scopus)

Abstract

Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders. Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA₁: bafilomycin A₁; BrdU: Bromodeoxyuridine/5-bromo-2ʹ-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3ʹ–diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.

Original language	English
Pages (from-to)	512-530
Number of pages	19
Journal	Autophagy
Volume	16
Issue number	3
DOIs	https://doi.org/10.1080/15548627.2019.1630222
Publication status	Published - 2020 Mar 3

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04].

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04]. We thank Drs. Masaaki Komatsu (Tokyo Metropolitan Institute of Medical Science, Japan) and Myung-Shik Lee (Yonsei University, Korea) for Atg7 fl/fl mice.

Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

Atg7 knockout
autophagic cell death
corticosterone
hippocampal neurogenesis
serum/glucocorticoid regulated kinase 3
stress

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1080/15548627.2019.1630222

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Jung, S., Choe, S., Woo, H., Jeong, H., An, H. K., Moon, H., Ryu, H. Y., Yeo, B. K., Lee, Y. W., Choi, H., Mun, J. Y., Sun, W., Choe, H. K., Kim, E. K., & Yu, S. W. (2020). Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits. Autophagy, 16(3), 512-530. https://doi.org/10.1080/15548627.2019.1630222

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abstract = "Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders. Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2ʹ-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3ʹ–diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.",

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author = "Seonghee Jung and Seongwon Choe and Hanwoong Woo and Hyeonjeong Jeong and An, {Hyun Kyu} and Hyewon Moon and Ryu, {Hye Young} and Yeo, {Bo Kyoung} and Lee, {Ye Won} and Hyosun Choi and Mun, {Ji Young} and Woong Sun and Choe, {Han Kyoung} and Kim, {Eun Kyoung} and Yu, {Seong Woon}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04]. Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04]. We thank Drs. Masaaki Komatsu (Tokyo Metropolitan Institute of Medical Science, Japan) and Myung-Shik Lee (Yonsei University, Korea) for Atg7 fl/fl mice. Publisher Copyright: {\textcopyright} 2019, {\textcopyright} 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.",

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doi = "10.1080/15548627.2019.1630222",

language = "English",

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T1 - Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits

AU - Jung, Seonghee

AU - Choe, Seongwon

AU - Woo, Hanwoong

AU - Jeong, Hyeonjeong

AU - An, Hyun Kyu

AU - Moon, Hyewon

AU - Ryu, Hye Young

AU - Yeo, Bo Kyoung

AU - Lee, Ye Won

AU - Choi, Hyosun

AU - Mun, Ji Young

AU - Sun, Woong

AU - Choe, Han Kyoung

AU - Kim, Eun Kyoung

AU - Yu, Seong Woon

N1 - Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04]. Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04]. We thank Drs. Masaaki Komatsu (Tokyo Metropolitan Institute of Medical Science, Japan) and Myung-Shik Lee (Yonsei University, Korea) for Atg7 fl/fl mice. Publisher Copyright: © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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Y1 - 2020/3/3

N2 - Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders. Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2ʹ-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3ʹ–diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.

AB - Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders. Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2ʹ-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3ʹ–diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.

KW - Atg7 knockout

KW - autophagic cell death

KW - corticosterone

KW - hippocampal neurogenesis

KW - serum/glucocorticoid regulated kinase 3

KW - stress

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U2 - 10.1080/15548627.2019.1630222

DO - 10.1080/15548627.2019.1630222

M3 - Article

C2 - 31234698

AN - SCOPUS:85068041136

SN - 1554-8627

VL - 16

SP - 512

EP - 530

JO - Autophagy

JF - Autophagy

IS - 3

ER -

Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits

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