Thymidine kinase 2 loss — the hallmark of thymidine kinase 2 deficiency (Tk2d) —appears to be a central driver of frequent epileptic seizures by linking impaired energy production to brain inflammation, according to a study published recently in Neuroscience.
In this detailed analysis of human epileptic brain tissue, researchers found that lower levels of the mitochondrial protein Tk2 were consistently associated with higher seizure frequency, regardless of where seizures originated in the brain.
The study analyzed surgically removed brain tissue from patients with temporal lobe epilepsy and from those with seizures arising outside the temporal lobe. Patients were further divided into high- and low-frequency seizure groups.
Although protein changes differed by brain region, a shared pattern emerged in patients with frequent seizures: Proteins required for mitochondrial function and energy metabolism were broadly reduced, while proteins linked to inflammation and cellular stress were increased.
Read more about causes and risk factors for Tk2d
Tk2d stood out among these changes. Tk2 is essential for maintaining mitochondrial DNA, which neurons rely on to generate ATP, the energy needed to stabilize electrical signaling. Across both epilepsy types, Tk2 levels showed a clear inverse relationship with seizure frequency. Patients with frequent seizures had significantly fewer Tk2-positive neurons, confirming that Tk2 deficiency is a feature of severe disease.
“These findings position Tk2 at the nexus of mitochondrial homeostasis and innate immune signaling, revealing a previously unrecognized dual role in epilepsy pathogenesis,” explained this study’s authors.
Results were reinforced in animal models. In mice with chemically induced epilepsy or post-traumatic seizures, Tk2d was observed in multiple seizure-related brain regions. When Tk2 levels were experimentally reduced in neurons, mitochondrial health declined, cell viability dropped and inflammatory pathways became highly active.
This inflammatory response was traced to activation of the cGAS-STING pathway, a cellular alarm system normally used to detect danger signals. Tk2d destabilizes mitochondrial DNA, allowing it to leak into the cell and trigger this immune response. In the brain, this process appears to increase neuronal excitability, making seizures more intense and more frequent.
For patients, these results help explain why repeated seizures can worsen over time. They suggest epilepsy is not only a disorder of abnormal electrical activity but also one of metabolic failure and chronic inflammation. Although these findings do not yet change clinical care, they highlight Tk2 and mitochondrial health as promising targets for future therapies aimed at reducing seizure frequency and improving long-term outcomes.
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