miRSodium · miRNA regulation of developmental sodium channel isoform transition and its implications for Dravet syndrome

miRNA regulation of developmental sodium channel isoform transition and its implications for Dravet syndrome

The miRSodium project focused on understanding how the levels of sodium ion channels are controlled in the developing brain and how this could be used for new therapies. Sodium ion channels are specialised proteins that allow the flow of ions in and out of cells and thus control how active nerve cells are and how they work together. Mutations in the gene SCN1A, which gives rise to one of these channels (sodium channel 1.1), cause a severe and rare form of epilepsy in children called Dravet syndrome (DS). Dravet syndrome leads to recurrent seizures, learning difficulties, developmental delay, other neurological problems and often sudden unexplained death in epilepsy (SUDEP) in children. Even though we know it is caused by a mutated gene SCN1A, we still do not understand a lot about how epilepsy works in people with DS, and there is no cure available. DS patients have the functional gene SCN3A producing a different version of the same channel. Around the age of 6 months, the expression of the channel from the defective SCN1A gene becomes dominant over SCN3A and causes abnormal neuronal function resulting in DS. Since children develop normally before the transition from functional SCN3A to non-functional SCN1A, we hypothesise that understanding how this transition in expression occurs can open new options for DS therapy. To explore this hypothesis, the miRSodium project focused on the involvement of small molecules called microRNAs (miRNAs) in the regulation of sodium channel production and their potential contribution to the transition between SCN1A and SCN3A. MicroRNAs are small naturally occurring molecules that control the activity of genes - they are molecular switches that can turn genes on or off. As the transition between sodium channel versions occurs across mammalian species, we studied its mechanism in the mouse model recapitulating DS symptoms (Scn1a+/-) and control animals without the mutated gene. Investigation in the animal model allows us to explore the activity of miRNAs and the targets under their control in young brains before and during the onset of DS symptoms (typically on day 17 in mice). We aim to investigate how specific miRNAs influence ion channels, with the goal of developing a novel treatment approach that can relieve symptoms of DS. Project Objectives: • Enhance our understanding of the molecular processes ongoing in DS. • Identify miRNAs that regulate sodium ion channels involved in DS. • Explore the impact of manipulating these miRNAs on the function of brain cells. • Test in a mouse model if the manipulation of these miRNAs leads to the reduction of DS symptoms.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз