<i>D2HGDH</i> Deficiency Regulates Seizures through GSH/Prdx6/ROS‐Mediated Excitatory Synaptic Activity
Current antiepileptic drugs are ineffective in one-third of patients with epilepsy; however, identification of genes involved in epilepsy can enable a precision medicine approach. Here, it is demonstrated that downregulating D-2-hydroxyglutarate dehydrogenase (D2HGDH) enhances susceptibility to epilepsy. Furthermore, its potential involvement in the seizure network through synaptic function modulation is investigated. D2HGDH knockdown reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio and elevates reactive oxygen species (ROS) levels within neurons. Oxidative stress may play a crucial role in the pathogenesis of epilepsy. The specific contribution of each pathway varies among patients, highlighting the complexity of this disease. In this study, downregulation of D2HGDH affects modulation of ROS levels, synaptic transmission, and seizure susceptibility. Furthermore, the acid calcium-independent phospholipase A2 (aiPLA2) inhibitor, MJ33, restores the GSH/GSSG balance and reverses the increase in ROS levels caused by D2HGDH knockdown, resulting in remission of epilepsy-related behaviors. The results demonstrate that downregulation of D2HGDH affects synaptic function by regulating ROS production. These findings support the use of targeted gene therapy as a potential alternative to antioxidant-based treatments for refractory epilepsy.
Authors
- Danmei Hu (ORCID: https://orcid.org/0000-0003-2325-4890)
- Xin Tian (ORCID: https://orcid.org/0000-0003-1552-8919)
- Patrick Kwan (ORCID: https://orcid.org/0000-0001-7310-276X)
- Zhijuan Zhang (ORCID: https://orcid.org/0000-0002-6058-6221)
- Peng Zhang (ORCID: https://orcid.org/0000-0002-9603-8454)
- Rong Li (ORCID: https://orcid.org/0000-0002-4465-3324)
- Jie Liu (ORCID: https://orcid.org/0000-0003-0451-6111)
- Jiyuan Li (ORCID: https://orcid.org/0000-0002-7462-6810)
- Jinyu Zhou (ORCID: https://orcid.org/0000-0002-4803-9559)
- Demei Xu
- Rui Huang (ORCID: https://orcid.org/0000-0003-1139-698X)
- Yuanlin Ma (ORCID: https://orcid.org/0000-0002-7811-7298)
- Chenlu Zhang (ORCID: https://orcid.org/0000-0003-4171-5099)
- Fenglin Tang
- Hui Zhang (ORCID: https://orcid.org/0000-0003-1520-2433)
Institutions
- Kunming University of Science and Technology (CN)
- Shanxi Medical University (CN)
- Dalian Medical University (CN)
- First People's Hospital of Yunnan Province (CN)
- Second Affiliated Hospital of Chongqing Medical University (CN)
- First Hospital of Shanxi Medical University (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Shanxi Academy of Medical Sciences (CN)
- Monash University (AU)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1002/advs.202404488
- Citations
- 3
- Primary Topic
- Amino Acid Enzymes and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.88
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Chongqing
- Centre Scientifique et Technique du Bâtiment