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  3. Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression

Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression

  • Cell Discov. 2023 Aug 29;9(1):90. doi: 10.1038/s41421-023-00583-7.
Shao-Qi Zhang # 1,  Qiao Deng # 1,  Qi Zhu # 2,  Zhuang-Li Hu 1 3 4 5,  Li-Hong Long 1 3 4 5,  Peng-Fei Wu 1 4 5,  Jin-Gang He 1 4 5,  Hong-Sheng Chen 1 3,  Zhenyu Yue 6,  Jia-Hong Lu 7,  Fang Wang 8 9 10 11,  Jian-Guo Chen 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Zhuhai, Macau SAR, China.
  • 3 The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China.
  • 4 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 5 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China.
  • 6 Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Zhuhai, Macau SAR, China. [email protected].
  • 8 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 9 The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China. [email protected].
  • 10 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 11 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China. [email protected].
  • 12 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 13 The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China. [email protected].
  • 14 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 15 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China. [email protected].
  • # Contributed equally.
PMID: 37644025 DOI: 10.1038/s41421-023-00583-7
Abstract

Dysfunctional Autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional Autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the Vps34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent Autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment.

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