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Super-resolution imaging to uncover microRNA control of astrocytes in epilepsy

Periodic Reporting for period 1 - AstroMiRimage (Super-resolution imaging to uncover microRNA control of astrocytes in epilepsy)

Reporting period: 2018-12-01 to 2020-11-30

AstroMiRimage aims at finding novel therapeutics for epilepsy, a chronic neurological disease characterised by recurrent epileptic seizures which affects more than 70 million people worldwide (six million in Europe). A diagnosis of epilepsy can have major implications on a person’s life, for example losing the right to drive or to exercise a profession. People with epilepsy are also at an increased risk of death.

Seizures are generally controllable using antiepileptic drugs. However, about 30% of people with epilepsy do not respond to commonly available drugs. Altogether, drug-refractory epilepsy is estimated to have a socio-economic burden of ~14 billion Euro per year in Europe. Therefore, there is an urgent unmet need to develop novel therapeutics for epilepsy.

All current antiepileptic drugs and also most pre-clinical therapies act on neurons, the cells in the brain that are responsible for electrical signal transmission and generation of seizures. Nevertheless, a universal hallmark of epileptic tissue is astrocyte dysfunction which has not received much attention as a therapeutic target. Astrocytes are a type of support cells in the brain, and they play important roles in the healthy and diseased brain.
The main objective of this project is to establish a novel treatment option that specifically targets astrocytes to prevent excessive network excitation and thus seizure generation.
AstroMiRimage is split into six specific Work Packages (WPs), three for research, one for communication, dissemination and exploitation, one for training/transfer of knowledge, and one for management of the project.
Through research in WPs 1, 2 and 3, the Fellow has isolated microRNAs (short non-coding RNAs that regulate gene expression post-transcriptionally by targeting mRNAs and preventing their translation) from synaptosomes. Synapses are the contact points between two neurons, and the majority of synapses across the brain are ensheathed by astrocytic processes. Targeting these microRNAs will influence astrocyte morphology and local translation which might allow the clearing of excess glutamate and potassium from the synaptic cleft and hence prevent seizure generation.

Throughout the project, the Fellow acquired training in several state-of-the-art techniques, including modelling epilepsy in mice, RNA isolation and sequencing, and super-resolution microscopy imaging.

In WP4, the Fellow communicated project findings via oral and poster presentations at nine national and international conferences and meetings. Furthermore, the Fellow participated in four public outreach activities to promote AstroMiRimage and to communicate findings to the general public.

In WP5, the Fellow gained transferable skills attending ten training workshops and multi-day conferences. The Fellow conducted research workshops with hands-on experience for researchers and provided supervision and mentoring for early career researchers and undergraduate students.

The impact of AstroMiRimage is further highlighted through the publication of three Open Access peer-reviewed articles in high impact journals, one article under review, and one article under preparation. The findings obtained over the course of this Fellowship will contribute to disease modifying therapies and improve the lives of people with epilepsy.
About one third of people with epilepsy does not respond to commonly available antiepileptic drugs, creating. Drug-refractory epilepsy is estimated to have a socio-economic burden of ~14 billion Euro per year in Europe. All current antiepileptic drugs and also most pre-clinical therapies act on neuronal targets – ion channels & neurotransmitter receptors. However, a universal hallmark of epileptic tissue is astrocyte dysfunction which has not received much attention as a therapeutic target. Three key roles of astroglia: rapid uptake of neurotransmitters such as glutamate, extracellular potassium buffering and release of gliotransmitters are disturbed in disease, leading to increased extracellular glutamate and potassium concentrations, which in turn mediate further neuronal depolarisation and seizures.

The promising findings acquired of the course of AstroMiRimage that microRNAs are deregulated in astrocyte processes in epilepsy have the potential to make a major contribution towards future epilepsy therapeutics.
Pint of Science Festival 2019; Dublin, Ireland
BNA 2019 Festival of Neuroscience; Dublin, Ireland