Deletion of SH2D5 alleviates epileptic seizures and NMDAR expression via autophagic degradation of STAT1

  • JCI Insight. 2025 Aug 22;10(16):e191347. doi: 10.1172/jci.insight.191347.
Haokun Guo  1  2  3  4 ,  Hui Zhang  2  3 ,  Chenlu Zhang  5 ,  Yuanyuan Shen  2 ,  Liumi Jiang  2  3 ,  Min Yang  2  3 ,  Yuansong Zhang  3  4  6 ,  Ningning Zhang  7 ,  Ruirui Zhang  7 ,  Ran Yu  8 ,  Yong Yang  8 ,  Xin Tian  1  2  3  4
Affiliations
  • 1. Department of Geriatrics.
  • 2. Department of Neurology, and.
  • 3. Department of Epilepsy Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4. Key Laboratory of Major Brain Disease and Aging Research, Ministry of Education, Chongqing Medical University, Chongqing, China.
  • 5. The First Clinical Medical College of Shanxi Medical University, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
  • 6. Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China.
  • 7. The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
  • 8. Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China.
PMID: 40857409 DOI: 10.1172/jci.insight.191347
Abstract

Epilepsy is a common neurological disorder resulting from an imbalance between neuronal excitation and inhibition. Synapses play a pivotal role in the pathogenesis of epilepsy. Src-homology 2 (SH2) domain-containing protein 5 (SH2D5) is highly expressed in the brain and is implicated in the regulation of synaptic function. However, its role and mechanism in epilepsy remain unclear. In this study, we found that SH2D5 was predominantly localized to pyramidal neurons in the mouse hippocampus and was upregulated in the hippocampus of epileptic brains. KO of Sh2d5 in the hippocampus alleviated both the susceptibility to and severity of epileptic activity. Mechanistically, SH2D5 regulated N-methyl-D-aspartate receptor-mediated (NMDAR-mediated) excitatory synaptic transmission by altering the protein expression levels of NMDAR subunits. We further demonstrated that SH2D5 modulated the transcription of NMDARs by promoting the autophagic degradation of STAT1. These findings suggest that targeting the SH2D5/STAT1/NMDAR pathway may offer a potential therapeutic strategy for epilepsy.

Keywords
Cell biology; Neurological disorders; Neuroscience; Synapses.
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