The Road Less Travelled: Exploring the profile and functions of non-coding RNAs in brain disease

Nearly 98 - 99% of the genome has little to no coding function and it is transcribed into non-coding RNAs (ncRNAs). These influence transcription, RNA processing and translation and include different sorts of molecules such as transfer RNAs (tRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs).
RNA metabolism is extremely relevant in the brain, as RNA is dynamically expressed and shows highly regulated temporal and spatial patterns, including tissue- and cell-type specificity. Research has shown that ncRNAs participate in several processes including brain development, synaptic plasticity, cell death, oxidative stress and epigenetic modifications. Importantly, their expression is often perturbed in tissues affected by neurological disorders (e.g. Alzheimer’s disease, Autism spectrum disorder, Huntington's disease, glioma) and accounts for an important layer of complexity when trying to dissect brain disease-mechanisms. Epilepsy is considered the most common chronic brain disease by affecting more than 50 million people globally. Currently, it is considered as a complex disorder likely resulting from the interplay between intrinsic (genetic) and extrinsic factors such as head trauma, infection episodes or brain tumours. Mesial temporal lobe epilepsy (mTLE) is a common form of focal epilepsy in which seizures originate from the amygdalo-hippocampal regions. An initial injury event (status epilepticus) is thought to trigger brain alterations (epileptogenesis, or ‘latent phase’) which will later develop into spontaneous seizures and, in some cases, hippocampal sclerosis. The initial treatment for the majority of epilepsy patients is based on antiepileptic drugs (AEDs). However, more than 30% of epilepsy patients continue to experience seizures despite AED treatment. This condition, known as ‘refractory epilepsy’, is present in 80% of mTLE patients. As a result, there is an urgent unmet need for innovative therapeutic approaches for treating refractory epilepsy. The pathological mechanisms leading to temporal lobe epilepsy (TLE) are not fully comprehended. The extensive use of animal models along with observations from human tissue have underlined important features. Common deregulated mechanisms include: neuronal loss, granule cell mossy fiber sprouting, activated astrocytes and microglia, decreased glutamine synthetase, down-regulation of ion channels and neurotransmitters, altered synaptic plasticity and dysfunction of the blood-brain barrier. These processes co-exist in the epileptic brain and ultimately lead to excitotoxicity and neuronal hyperexcitability. How altered ncRNA expression influences these processes remains elusive.
In this dissertation, we aimed to explore the profile and function of the non-coding transcriptome in the healthy and diseased brain. Individually, the chapters in this dissertation illustrate how different ncRNA classes may contribute to disease-related mechanisms. Together, they provide a framework to rethink novel therapeutic approaches for brain disease which remain untreatable or associated with poor treatment outcomes.