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

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

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 susceptibilit...

Full description

Saved in:
Bibliographic Details
Main Authors: Zhijuan Zhang, Hui Zhang, Peng Zhang, Rong Li, Jinyu Zhou, Jiyuan Li, Danmei Hu, Rui Huang, Fenglin Tang, Jie Liu, Demei Xu, Chenlu Zhang, Xin Tian, Yuanlin Ma, Patrick Kwan
Format: Article
Language:English
Published: Wiley 2025-04-01
Series:Advanced Science
Subjects:
D‐2‐hydroxyglutarate dehydrogenase
epilepsy
excitatory synapses
reactive oxygen species
Online Access:https://doi.org/10.1002/advs.202404488
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2198-3844

Similar Items