Authors :
Presenting Author: Theresa Auer, MSc – University College Dublin
Morten Venø, PhD – PostDoc, Aarhus University; David Henshall, PhD – Professor, Royal College of Surgeons Dublin; Rory Johnson, PhD – Assoc Prof, University College Dublin; Cristina Reschke, PhD – Lecturer, Royal College of Surgeons Dublin; Gary Brennan, PhD – Asst Prof, University College Dublin
Rationale:
Development of temporal lobe epilepsy (TLE) after a precipitating brain insult is associated with large-scale changes in epigenetic-mediated regulation of gene expression. This altered epigenome is a known critical driver for many epileptogenic processes. In contrast to other epigenetic mechanisms such as DNA methylation and microRNAs, the functional involvement of long non-coding RNAs (lncRNAs) in the pathogenesis of epilepsy remains largely unexplored, although they are increasingly recognized as key modulators of RNA processing at the (post)-transcriptional level. Here, we perform the first comprehensive profiling study of lncRNAs in epilepsy development and progression and assess their utility as novel drug targets.
Methods:
To study the role of lncRNA dysregulation in TLE, kainic acid-induced post-
Status Epilepticus mouse models were used. We profiled genome-wide lncRNA expression by performing Next Generation Sequencing on hippocampal brain tissue collected at key timepoints during epileptogenesis. Applying a stringent bioinformatic filtering approach we predicted those dysregulated lncRNAs with the highest pro-epileptogenic potential in humans and are currently assessing the effects of targeted lncRNA inhibition with encouraging preliminary results.
Results:
Transcriptomic analysis revealed significant changes in numerous lncRNAs strongly influenced by the time after the initial insult. Several of them are known for their importance during embryonic development, in plasticity and cell death, which indicates lncRNA-mediated effects on major epileptogenic disease mechanisms. Based on various characteristics including the expression level, expression change and inter-species conservation, we selected the five most promising lncRNA candidates and successfully achieved their target-specific downregulation using antisense oligonucleotides. These oligonucleotides are now being used to investigate the disease-modifying potential of targeting dysregulated lncRNAs in vivo and to explore the underlying molecular mechanisms of action in vitro.
Conclusions:
Epileptogenesis is characterized by extensive dysregulation of lncRNA expression, which is a likely contributor to many epileptogenic processes such as synaptic reorganization and cell loss. This renders lncRNAs promising targets for the development of innovative therapeutic and/or preventative treatment approaches.
Funding:
This project is supported by the HRB-HRCI Joint funding scheme and UCD Ad Astra funding.