Deletion of SH2D5 alleviates epileptic seizures and NMDAR expression via autophagic degradation of STAT1
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.
Authors
- Yuanyuan Shen (ORCID: https://orcid.org/0009-0004-1832-1168)
- Ran Yu (ORCID: https://orcid.org/0000-0002-7692-1071)
- Haokun Guo
- Xin Tian (ORCID: https://orcid.org/0000-0003-1552-8919)
- Liumi Jiang
- Yong Yang (ORCID: https://orcid.org/0000-0002-9094-7868)
- Hui Zhang (ORCID: https://orcid.org/0000-0002-0843-399X)
- Ning‐Ning Zhang (ORCID: https://orcid.org/0000-0002-3872-7884)
- Ruirui Zhang (ORCID: https://orcid.org/0000-0001-6392-3898)
- Min Yang (ORCID: https://orcid.org/0000-0003-3727-3654)
- Chenlu Zhang (ORCID: https://orcid.org/0000-0003-4171-5099)
- Yihong Zhang (ORCID: https://orcid.org/0000-0002-6432-3840)
Institutions
- Qingdao University (CN)
- British Geriatrics Society (GB)
- Affiliated Hospital of Qingdao University (CN)
- Lanzhou University Second Hospital (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Lanzhou University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1172/jci.insight.191347
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Chongqing Medical University
- Natural Science Foundation of Chongqing
- Qingdao University
- Centre Scientifique et Technique du Bâtiment