Translational control in focal cortical malformations and epilepsy

PROJECT SUMMARY Focal cortical dysplasia type II (FCDII) is a neurodevelopmental disorder caused by brain somatic variants in the mTOR signaling pathway, leading to focal cortical malformations and seizures that are largely resistant to medical treatment. Previous research has provided insights into how dysregulated mTOR signaling contributes to abnormal brain development and the formation of hyperexcitable brain networks in FCDII, however, the precise mechanisms of epileptogenesis are not fully understood. Recent studies have shown that disrupted eIF4E-mediated translational control, downstream of mTOR, is essential to FCDII pathogenesis. eIF4E is the rate-limiting protein in translational initiation, and its functions are regulated through two known mechanisms: inhibitory binding by 4E-BPs or phosphorylation by MNK kinases. Dysregulated 4E-BP-eIF4E signaling has been implicated in FCDII pathogenesis, but the role of the MNK-eIF4E axis is unknown. Transcriptomic studies have shown that eIF4E phosphorylation preferentially enhances the translation of specific mRNAs, including those involved in neural plasticity and function. This led to the hypothesis that MNK-eIF4E-mediated translational dysregulation contributes to focal cortical malformation and seizures in FCDII by altering the translation of mRNA subsets involved in cortical development and neuronal function. This project seeks to address this hypothesis by combining cell-type specific translatomic analyses, biochemical and histological interrogations, genetic and pharmacological manipulations, and EEG in FCDII mouse models expressing mTOR pathway variants. The specific aims are to: 1) determine the specific mRNA subsets that are altered due to dysregulated MNK-eIF4E signaling in FCDII, 2) delineate the contribution of MNK-eIF4E dysregulation to FCDII lesion development, and 3) test the impact of genetic and pharmacological inhibition of MNKs on FCDII-associated seizures. The results from these studies will advance our understanding of the cellular and molecular mechanisms leading to severe pediatric epilepsy and help guide new therapeutic strategies to treat, modify, or prevent intractable epilepsy in FCDII and potentially other seizure disorders with shared etiology.