Epilepsy is a chronic, devastating illness characterised by spontaneous recurrent seizures and often accompanied by debilitating cognitive impairment. Epilepsy can be described as a network disorder and changes in the properties which compose these networks constitutes a critical mechanism of disease development. Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is usually precipitated by brain insults such as traumatic brain injury, stroke or status epilepticus. These brain insults trigger large scale changes in gene expression and gene expression regulation which then give rise to the altered cellular properties which culminate in seizure activity. Up to one third of individuals with TLE are drug resistant.
Large scale changes in gene expression and regulation is seen at the epigenetic, transcriptional and posttranscriptional levels. We recently discovered that changes in RNA methylation (an important post-transcriptional mechanism of gene regulation) are prominent in human TLE and may represent an additional, and yet, unexplored layer of gene regulation which may be involved in the disease.
We have found that hypomethylation of RNA in human temporal lobe epilepsy promotes the translation of epilepsy-related transcripts which may drive the pathogenesis of the disease. Additionally blocking the deposition of m6A by inhibiting METTL3 exacerbates epilepsy development in mice. Thus we now propose that blocking hypomethylation of mRNAs by inhibiting the main demethylase enzyme, FTO, may prevent epilepsy development by halting the translation of epilepsy-associated proteins. To do this we use a combination of pre-clinical and human epilepsy models combined with large scale sequencing to elucidate the precise effect of m6A on translational dynamics in epilepsy.
It is thought that this project will i) illuminate novel mechanisms of epileptogenesis. ii) assess the therapeutic validity of targeting aberrant gene networks to prevent or treat epilepsy.