Identifying Causes of Drug-Resistant Epilepsy... Clues to New Treatments

KAIST Discovers 'MTOR Gene Mutation' Through Interdisciplinary Research Across Three Departments

[Asia Economy Reporter Kim Bong-su] Domestic researchers have identified the cause of a specific drug-resistant epilepsy, signaling a breakthrough in developing treatments.

The Korea Advanced Institute of Science and Technology (KAIST) announced on the 25th that a joint research team consisting of Professor Lee Jeong-ho from the Graduate School of Medical Science and Engineering, Professor Park Se-beom from the Department of Bio and Brain Engineering, and Professor Son Jong-woo from the Department of Life Sciences has elucidated the mechanism by which epilepsy with high drug resistance occurs due to mutations in the MTOR gene.

This study confirmed the specific mechanism by which mutations occurring in a very small number of neurons lead to a hyperactive state of neural networks, providing new insights into the causes of epilepsy and the development of treatments.

Epilepsy, also known as ganjil, is one of the representative neurological disorders that widely affects children and young adults. It has been actively studied across medical and neuroscience fields due to not only social stigma but also its potential to cause sudden death in severe cases. In particular, focal cortical dysplasia (FCD) is one of the most common causes of epilepsy but shows resistance to drug treatment, causing suffering for patients and their caregivers.

The KAIST interdisciplinary research team achieved comprehensive explanations of the complex mechanisms of epilepsy onset through a multidisciplinary approach. Their research spanned from intracellular genetic perspectives to electrophysiology of single neurons, networks of brain tissue in close proximity, and neural networks at the whole-brain level through various experiments and simulations.

Focal cortical dysplasia is a disorder caused by somatic mutations in the mTOR pathway (MTOR, TSC, DEPDC5) in some neural stem cells during cerebral development. It is one of the common causes of epilepsy and is difficult to treat due to poor response to antiepileptic drugs. The research team used animal models with the same disease as actual tissue from patients with focal cortical dysplasia to elucidate the specific principles by which somatic mutations in individual neurons lead to seizure activity at the neural network level.

The team first discovered that these somatic mutations occur in a small number of neurons, less than 5% of brain tissue, and that the electrical properties of these neurons differ from those of normal cells. However, simulations of overall neural network activity, including the majority of normal cells, showed that since these mutations were limited to a very small proportion of neurons, changes in the electrical properties of these cells alone did not lead to abnormal activity in the entire neural network, failing to explain the seizure activity observed at the network level in epilepsy.

Through follow-up experiments, the team found that the hyperactivity capable of inducing epileptic seizures was generated not by neurons with MTOR somatic mutations but by neighboring non-mutated neurons. This means that the activity of neurons with gene mutations is not the direct cause of epilepsy; rather, these cells induce specific changes in the majority of surrounding non-mutated neurons, leading to seizure activity at the whole neural network level. This is an example of non-cell autonomous hyperexcitability caused by brain somatic mutations.

Building on this, additional animal experiments and studies using post-surgical patient brain tissue revealed that cells with MTOR somatic mutations overexpress the adenosine kinase (ADK) gene. Furthermore, this disrupts the network system of the majority of surrounding non-mutated neurons, inducing hyperactivity that ultimately leads to excessive activity at the whole neural network level.

The research team stated, "This study provides deeper insight into the causes of drug-resistant epilepsy, which has been difficult to manage effectively with existing treatments," and added, "It is a good example of effective collaborative research offering solutions through a multidisciplinary approach spanning genomics, neurobiology, and computational neuroscience to address problems that are difficult to solve with experiments or research techniques from a single field."

The research findings were published on the 29th of last month in the international neurology journal Annals of Neurology.

This content was produced with the assistance of AI translation services.