2. Academic Validation
  3. circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling

circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling

  • Genes Dis. 2025 Jun 18;13(2):101718. doi: 10.1016/j.gendis.2025.101718.
Dandan Xu 1,  Zihan Huang 2,  Gaojia Zhang 1 3,  Jiao Jiao 1,  Yujia Cao 1,  Mengyu Liu 1,  Yan Kong 2,  Zhijun Zhang 1 4
Affiliations

Affiliations

  • 1 Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
  • 3 Department of Psychology and Sleep Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230061, China.
  • 4 Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen University of Technology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
PMID: 41459113 DOI: 10.1016/j.gendis.2025.101718
Abstract

Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal Autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal Autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal Autophagy.

Keywords

Autophagy; Dopamine D3 receptor; Major depressive disorder; circRNA-encoded protein; circRNAs.

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