2. Academic Validation
  3. Cathepsin B deficiency disrupts cortical development via PEG3, leading to depression-like behavior

Cathepsin B deficiency disrupts cortical development via PEG3, leading to depression-like behavior

  • Commun Biol. 2025 Jul 23;8(1):1097. doi: 10.1038/s42003-025-08508-8.
Zhen Xie # 1 2,  Qinghu Yang # 3,  Fei Lan 2,  Wei Kong 2,  Shuxuan Zhao 2,  Jinyi Sun 4,  Yan Yan 5,  Zhenzhen Quan 2,  Zhantao Bai 6,  Hong Qing 7,  Jian Mao 8,  Junjun Ni 9
Affiliations

Affiliations

  • 1 Beijing Life Science Academy (BLSA), Beijing, China.
  • 2 Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China.
  • 3 Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan'an University, Yan'an, China.
  • 4 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 5 Department of Cardiology, The First Hospital of Hebei Medical University, Shijiazhuang, China.
  • 6 Research Center for Resource Peptide Drugs, Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources, Yan'an University, Yan'an, China. [email protected].
  • 7 Department of Biology, Shenzhen MSU-BIT University, Shenzhen, China. [email protected].
  • 8 Beijing Life Science Academy (BLSA), Beijing, China. [email protected].
  • 9 Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 40702210 DOI: 10.1038/s42003-025-08508-8
Abstract

Cathepsin B (CatB), a protease in endosomal and lysosomal compartments, plays a key role in neuronal protein processing and degradation, but its function in brain development remains unclear. In this study, we found that CatB is highly expressed in the cortex of E12.5-E16.5 mice. Morphological analysis revealed significant defects in cortical development in CatB knockout (KO) mice, particularly in layer 6. In vitro experiments showed that CatB deficiency notably impaired neuronal migration and development. Behaviorally, CatB KO mice displayed prominent depressive-like behaviors, and electrophysiological recordings demonstrated significantly reduced neuronal activity in layer 6 of the medial prefrontal cortex. Mechanistically, proteomics analysis revealed that CatB KO affected neuronal migration and axonal growth, and decreased the expression of key transcription factors involved in neuronal development, particularly PEG3. Deficiency of PEG3 also significantly impaired neuronal migration and development. Our findings uncover a role for CatB in cortical development and suggest a mechanism linking CatB deficiency with depression and developmental defects through the destabilization of PEG3.

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