2. Academic Validation
  3. Liquid-liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A

Liquid-liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A

  • Int J Biol Macromol. 2025 May;310(Pt 2):142986. doi: 10.1016/j.ijbiomac.2025.142986.
Xiaowen Yang 1,  Lin Wei 2,  Saifeng Zhong 3,  Qiguang Wang 4,  Yujun Zhang 4,  Yonggang Zhang 5,  Aiqing Yu 6
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Taihe Hospital, The Affiliated Hospital of Hubei University of Medicine, Shiyan 442000, China; Department of Clinical Laboratory, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University/Department of Laboratory Medicine of School of Medicine, Hunan Normal University, Changsha 410000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China.
  • 2 Department of Clinical Laboratory, Taihe Hospital, The Affiliated Hospital of Hubei University of Medicine, Shiyan 442000, China.
  • 3 Department of Clinical Laboratory, Shaoyang central hospital, The Affiliated Hospital of Nanhua University, Shaoyang 422000, China.
  • 4 Department of Clinical Laboratory, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University/Department of Laboratory Medicine of School of Medicine, Hunan Normal University, Changsha 410000, China.
  • 5 Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Shenzhen 518000, China.
  • 6 Department of Clinical Laboratory, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University/Department of Laboratory Medicine of School of Medicine, Hunan Normal University, Changsha 410000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China. Electronic address: Yaq1989@hunnu.edu.cn.
PMID: 40216137 DOI: 10.1016/j.ijbiomac.2025.142986
Abstract

Microglia play an important role in hippocampus-dependent memory and cognitive function. Microglial aging contributes to hippocampal aging and influences neurodegenerative diseases, although the underlying mechanisms remain unclear. RBM33 was highly expressed in the hippocampus of naturally aged mice and senescent microglia. Hippocampus-specific genetic deletion of RBM33 alleviated age-related declines in learning and memory in aged RBM33 knockout (RBM33-/-) mice. In contrast, hippocampus-specific overexpression of RBM33 exacerbated these declines in aged RBM33 overexpression (RBM33Tg) mice, indicating that RBM33 acts as an age-promoting factor in the hippocampus. Mechanistically, RBM33 forms liquid-liquid phase separation (LLPS) both in vitro and in cells. RBM33 LLPS is required for its binding to the CDKN1A (p21cip1) promoter in a non-canonical transcriptional regulatory manner, leading to hippocampus-dependent declines in learning and memory by inducing microglial senescence. This study reveals that the RBM33 LLPS/ p21cip1 axis facilitates brain aging by inducing microglial senescence. Targeting the RBM33 LLPS/ p21cip1 axis may represent a therapeutic strategy to mitigate microglia senescence-mediated brain aging and hippocampus-dependent cognitive decline.

Keywords

Hippocampus aging; Microglial senescence; RBM33.

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