Emerging roles of long non‐coding RNAs in human epilepsy

Abstract

AbstractGenome‐scale biological studies conducted in the post‐genomic era have revealed that two‐thirds of human genes do not encode proteins. Most functional non‐coding RNA transcripts in humans are products of long non‐coding RNA (lncRNA) genes, an abundant but still poorly understood class of human genes. As a result of their fundamental and multitasking regulatory roles, lncRNAs are associated with a wide range of human diseases, including neurological disorders. Approximately 40% of lncRNAs are specifically expressed in the brain, and many of them exhibit distinct spatiotemporal patterns of expression. Comparative genomics approaches have determined that 65%–75% of human lncRNA genes are primate‐specific and hence can be posited as a contributing potential cause of the higher‐order complexity of primates, including human, brains relative to those of other mammals. Although lncRNAs present important mechanistic examples of epileptogenic functions, the human/primate specificity of lncRNAs questions their relevance in rodent models. Here, we present an in‐depth review that supports the contention that human lncRNAs are direct contributors to the etiology and pathogenesis of human epilepsy, as a means to accelerate the integration of lncRNAs into clinical practice as potential diagnostic biomarkers and therapeutic targets. Meta‐analytically, the major finding of our review is the commonality of lncRNAs in epilepsy and cancer pathogenesis through mitogen‐activated protein kinase (MAPK)‐related pathways. In addition, neuroinflammation may be a relevant part of the common pathophysiology of cancer and epilepsy. LncRNAs affect neuroinflammation‐related signaling pathways such as nuclear factor kappa‐ light‐ chain‐ enhancer of activated B cells (NF‐κB), Notch, and phosphatidylinositol 3‐ kinase/ protein kinase B (Akt) (PI3K/AKT), with the NF‐κB pathway being the most common. Besides the controversy over lncRNA research in non‐primate models, whether neuroinflammation is triggered by injury and/or central nervous system (CNS) toxicity during epilepsy modeling in animals or is a direct consequence of epilepsy pathophysiology needs to be considered meticulously in future studies.