Researchers Uncover Novel Actin-Mitochondria-Glutamate Pathway Driving Epilepsy, Opening New Avenues for Genetic Diagnosis and Treatment
核心洞察
Researchers at Baylor College of Medicine and the Duncan NRI have identified a novel actin-mitochondria-glutamate (AMG) biological pathway that can cause seizures when disrupted.
The study demonstrates that epilepsy (搜索) can result from specific combinations of two or more defective genes, not just single-gene mutations, explaining many previously undiagnosed cases.
In fruit fly models, drugs targeting mitochondrial fragmentation (Mdivi-1) and reactive oxygen species (NACA) significantly suppressed seizures, suggesting new therapeutic strategies.
Researchers at Baylor College of Medicine and the Duncan Neurological Research Institute (搜索) (Duncan NRI) at Texas Children's Hospital have uncovered a novel biological pathway that can lead to seizures when disrupted, according to a study published in the Journal of Clinical Investigation. The discovery challenges the traditional understanding that epilepsy (搜索) arises solely from defects in single genes, revealing instead that specific combinations of two or more defective genes can trigger the condition.
Epilepsy (搜索) affects approximately 50 million people worldwide — roughly 1 in every 130 people — yet more than half of patients with a suspected genetic cause remain without a genetic diagnosis. "Although scientists have discovered more than 1,000 genes that can individually cause epilepsy when disrupted, more than half of patients with a suspected genetic cause have no genetic diagnosis," said corresponding author Dr. Hugo Bellen, Distinguished Service Professor of the Department of Molecular and Human Genetics at Baylor and chair in neurogenetics at the Duncan NRI.
From Actin Biology to Seizures: Tracing a New Pathway
The research team, led by first author Dr. Shenzhao Lu, instructor of molecular and human genetics in the Bellen lab, focused on a group of seizure-associated genes involved in actin biology. Actin is a protein present in all cells that forms filaments serving as the foundation for the cytoskeleton — structures essential for cell adhesion, motility, and intracellular transport.
In 2022, Lu and colleagues first established an association between defective variants of the human gene TIAM1 (搜索) and a neurological disorder with seizures. The TIAM1 protein is abundant in neurons, where it helps regulate actin filament formation. In the current study, the team used the laboratory fruit fly to investigate how a defective TIAM1 gene — called sif in flies — could lead to epilepsy (搜索).
"We found that sif mutant flies have seizures," Lu said. "These flies make defective actin filaments that are shorter than those in normal flies and accumulate in clusters inside neurons. We observe this in fruit fly and human cells." Notably, the defect primarily affected glutamatergic neurons — excitatory neurons that produce the chemical messenger glutamate.
An Unexpected Mechanism: Mitochondria and Reactive Oxygen Species
Contrary to expectations, neurons lacking the sif gene were not structurally different from normal neurons, yet they were overly active. "If their structure and connections seemed normal, what was causing the seizures?" Lu asked.
The answer emerged from the connection between actin and mitochondrial division. The researchers observed that neurons with defective actin filaments had more mitochondria that were smaller than normal, more active, and producing higher levels of reactive oxygen species (ROS). "Too much ROS can lead to increased glutamatergic transmission and then seizures," Lu explained.
These findings delineate what the team has termed the actin-mitochondria-glutamate (AMG) pathway, a novel mechanism involving epilepsy (搜索)-associated actin regulatory genes.
Therapeutic Implications and Drug Responses
The study demonstrated that pharmacological interventions targeting components of the AMG pathway can reduce seizures in the fruit fly model. Preventing mitochondrial fragmentation with the drug Mdivi-1 significantly suppressed seizures in sif mutants. Additionally, treating sif mutants with NACA, an anti-ROS drug, reduced seizures and suppressed increased glutamatergic transmission.
A New Framework for Genetic Diagnosis
Perhaps most significantly, the team showed that combining two defective genes within the AMG pathway can cause seizures. "People with epilepsy (搜索) of unknown origin show more defective AMG genes when compared to people without the condition," Bellen said. "Modeling of these gene combinations observed in patients in the fruit fly confirmed that many of them increase the susceptibility to seizures."
The findings provide a new approach to improve genetic diagnosis for the substantial proportion of epilepsy (搜索) patients currently without answers. "Altogether, the findings show a novel biological pathway that can lead to seizures when disrupted and can be used to identify pairs of seizure-associated genes for improved diagnosis," Bellen added. "The novel mechanism also suggests potential therapeutic targets."
The study was supported in part by NIH grant U01 AG072439, the Huffington Foundation, the Neurogenetics Chair of the NRI, an NRI Zoghbi Scholar Award, the TNPO2 Foundation, the BrightFocus Foundation, the Effie Marie Cain Chair in Alzheimer's Disease Research at Baylor College of Medicine, the Huffington Foundation Chair in Parkinson's Disease Research at Texas Children's Hospital, the German Research Foundation, a Walter Benjamin Fellowship, and the Cancer Prevention and Research Institute of Texas award CPRIT RP240131.