Lack of CLOCK triggers epilepsy, study suggests


Published in the October 11 issue of the journal Neuron, a study reveals that loss of a protein called CLOCK leads to abnormalities in brain circuits that trigger epilepsy.

The study is led by Dr. Judy Liu at Children's National Medical Center. Some scientists from the University of Colorado Anschutz Medical Campus, the University of Virginia Health System, Georgetown University, and Virginia Tech Carillion Research Institute have also been involved in this work.

Epilepsy is a brain disorder that causes seizures, the severity of which ranges from mild to serious. A seizure event is characterized by an abnormal and excessive excitation of brain neurons. Many factors can trigger epilepsy, such as metabolic disorders of neurons, brain trauma, hemorrhage, ischemia, anoxia, infection and hyperthermia. But the molecular mechanisms of refractory focal epilepsy have not been fully elucidated. For patients with epilepsy who respond poorly to drug treatments, surgical removal of the brain area where seizures arise represents another treatment option.

To better understand epilepsy pathogenesis, Dr. Liu and colleagues studied epileptogenic tissues removed from patients with epilepsy. Transcriptome analysis of the tissues revealed a significant decrease in the expression of the CLOCK protein.

To further explore the role of CLOCK, the researchers used mice in which the CLOCK gene was deleted either in excitatory or inhibitory neurons. The mice lacking CLOCK in excitatory neurons exhibited increased susceptibility to seizures, particularly during sleep.

These results indicate that disruption of CLOCK may contribute to generation of epilepsy.

The CLOCK protein is known to regulate the circadian rhythm, a cycle that tells the body when to sleep, rise, eat, etc. CLOCK functions as a transcription factor, and disruption of CLOCK may downregulate the transcriptional products normally upregulated by CLOCK.

More research is needed to see how CLOCK and associated proteins affect the development of epilepsy. Such research would lead to novel therapeutic targets for the disorder.
 
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