2. Academic Validation
  3. D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS-Mediated Excitatory Synaptic Activity

D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS-Mediated Excitatory Synaptic Activity

  • Adv Sci (Weinh). 2025 Apr;12(13):e2404488. doi: 10.1002/advs.202404488.
Zhijuan Zhang 1,  Hui Zhang 1,  Peng Zhang 2,  Rong Li 3 4,  Jinyu Zhou 2,  Jiyuan Li 5,  Danmei Hu 6,  Rui Huang 1,  Fenglin Tang 1,  Jie Liu 1,  Demei Xu 1,  Chenlu Zhang 5,  Xin Tian 1 7,  Yuanlin Ma 1 7,  Patrick Kwan 1 8
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, 400016, China.
  • 2 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, 400010, China.
  • 3 Department of Neurology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, China.
  • 4 Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, First People's Hospital of Yunnan Province, Kunming, 650051, China.
  • 5 Department of Neurology, The First Hospital of Shanxi Medical University, Shanxi, 030012, China.
  • 6 Department of Neurology, Shanxi Bethune Hospital, Shanxi, 030032, China.
  • 7 Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
  • 8 Department of Neuroscience, Central Clinical School, Monash University, Melbourne, 3004, Australia.
PMID: 39739583 DOI: 10.1002/advs.202404488
Abstract

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.

Keywords

D‐2‐hydroxyglutarate dehydrogenase; epilepsy; excitatory synapses; reactive oxygen species.

Figures
Products