TRP53/p53 protects adult hippocampal neural stem cells from psychological stress by preventing autophagic cell death

Abstract

Psychological stress impairs adult hippocampal neurogenesis (AHN) and contributes to cognitive dysfunction. Previously, we reported that chronic psychological stress or the stress hormone corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem cells (ahNSCs). However, the regulatory mechanisms underlying this process remain largely unknown. The tumor suppressor gene Trp53/p53 is abundantly expressed in ahNSCs, yet its function under stress conditions has not been fully elucidated. Here, we demonstrate that, contrary to its well-established pro-apoptotic role, TRP53 acts as a survival factor that protects ahNSCs from stress-induced ACD. Conditional deletion of Trp53 in neural stem cells heightened vulnerability to chronic restraint stress (CRS), resulting in worsened memory deficits and mood disturbances compared to wild-type controls. Mechanistically, CORT facilitated MAP1LC3/LC3-mediated autophagic degradation of TRP53 through its LC3-interacting region (LIR), thereby promoting ACD. However, overexpression of either wild-type TRP53 or a degradation-resistant LIR mutant suppressed ACD by interfering with the ATG14-containing PIK3C3/VPS34 complex. Moreover, treatment with RITA, a small-molecule activator of TRP53, disrupted the TRP53-LC3 interaction, stabilized TRP53 levels, and protected ahNSCs from ACD, ultimately preventing CRS-induced cognitive impairment in the hippocampus. These findings identify TRP53 as a key negative regulator of ACD in ahNSCs and suggest that TRP53-stabilizing small molecules could represent a novel class of antidepressant therapies by preserving AHN. Abbreviations: ahNSC: adult hippocampal neural stem cell; AHN: adult hippocampal neurogenesis; ACD: autophagic cell death; BafA1: bafilomycin A1; ACTB actin, beta; CRS chronic restraint stress; c.CASP3: cleaved caspase 3; cKO conditional knockout; CORT: corticosterone; DG: dentate gyrus; i.p: intraperitoneal; KO: knockout; LABORAS: Laboratory Behavior Observation Registration and Analysis System; LIR LC3-interacting region; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MDM2: MDM2 proto-oncogene; NSC: neural stem cell; PFA: paraformaldehyde; PLA: proximity ligation assay; RITA: reactivation of TRP53 and induction of tumor cell apoptosis; SGK: serum/glucocorticoid regulated kinase; SGZ: subgranular zone; STS: staurosporine; TAM: tamoxifen; TRP53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UVRAG: UV radiation resistance associated.