Rescuing epilepsy associated with SYN1 gene mutations by inhibiting eEF2K/eEF2 pathway

Epilepsy is one of the most common neurological diseases. Although a plethora of pharmacological agents for the treatment of epilepsy are available, the disease cannot be adequately controlled in a relevant percentage of patients. In addition, the available drugs are directed at controlling symptoms, but leave the underlying progression of the disease unaltered. An array of mutations in the Synapsin (SYN) genes in humans has been associated with epilepsy and/or autism spectrum disorders. The human pathology has been well photocopied in mice (the Syn KO mice) in which the Syn genes have been inactivated. These mice are severely epileptic, because of an unbalance between inhibitory and excitatory synaptic transmission in the brain. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is a highly regulated, ubiquitous enzyme involved in the control of protein translation. Our recent data suggest that the eEF2K/eEF2 pathway regulates, at the protein translation level, the excitatory/inhibitory balance in the brain, and that inhibition of this pathway pushes the balance towards the inhibitory component. Interestingly, when we crossed mice in which eEF2K gene has been inactivated (eEF2K-KO mice) with Syn I KO mice we were able to strongly reduce the brain epileptic activity present in the Syn I KO animal, suggesting that the eEF2K/eEF2 pathway may represent a druggable target for the treatment of epilepsy. We will use Syn I KO mice where the expression if eEF2K will been genetically deleted or the enzyme activity will be pharmacologically inhibited to characterize the eEF2K/eEF2 pathway and rescue epilepsy in genetic mouse models. With this project we aim to fully test the hypothesis that eEF2K is a novel and non canonical pharmacological target to treat severe genetic forms of epilepsy.