4.7 Article

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

Journal

CELL DISCOVERY
Volume 9, Issue 1, Pages -

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SPRINGERNATURE
DOI: 10.1038/s41421-023-00583-7

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This study reveals the important role of dysfunctional autophagy in the pathogenesis of major depressive disorder (MDD). The expression of NRBF2 is attenuated in the dentate gyrus (DG) under chronic stress and its deficiency impairs autophagic flux in adult neural stem cells (aNSCs). Loss of NRBF2 disrupts the neurogenesis-related protein network and leads to the depression-like phenotype, while overexpressing NRBF2 rescues impaired adult hippocampal neurogenesis (AHN) and depression-like phenotype in mice.
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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