**Abstract**

Advancements in RNA sequencing technologies in recent years have contributed greatly to our understanding of the transcriptome and the now widely recognized multifaceted functions of RNA. The discovery and functional analysis of an increasing number of novel small non-coding RNAs (ncRNAs) has highlighted their importance as critical regulators of gene expression and brain function. In particular, two diverse classes of ncRNAs, microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs), are especially abundant in the nervous system and play roles in regulation of gene expression and protein translation, cellular stress responses and complex underlying pathophysiology of neurological diseases. This chapter will discuss the most recent findings highlighting the dysregulation, functions and regulatory roles of ncRNAs in the pathophysiological mechanisms of neurological disorders and their relevance as novel biomarkers of injury and therapeutic agents.

**Keywords:** non-coding RNA (ncRNA), microRNA (miRNA), tRNA-derived small RNAs (tsRNA), tRNA-derived stress-induced RNA (tiRNA), tRNA fragments (tRFs), epigenetics, molecular biology, neurological disorders

## **1. Introduction**

Normal neuronal function and development is reliant on tightly controlled regulation of gene expression at many levels. Advancements in transcriptomics and functional validation has elucidated key biological roles for non-coding RNAs (ncRNAs), transcripts do not encode proteins, in the regulation of a wide range of neuronal functions and pathophysiological processes. Over the past two decades large international collaborative research efforts such as the Human Genome Project and the ENCODE (Encyclopedia of DNA Elements) project have estimated that approximately 80% of the mammalian genome transcribes ncRNA and that 97% of RNA transcripts in the cell are non-coding [1–3]. This remarkable and unexplored area of molecular biology has since yielded many more types of ncRNA that have been shown to play a crucial role in a variety of biological processes.

ncRNA are classified either by their length or by functionality (**Table 1**). Small ncRNA are considered transcripts <200 nucleotides (nts) in length and long ncRNA are those >200 nts. Housekeeping ncRNA are constitutively expressed and are involved in mechanisms of cellular activity that are vital for cell viability. These include rRNA, tRNA and the more recently identified small nuclear RNA (snRNA), small nucleolar RNA (snoRNA) and telomerase RNA (TERC). Regulatory ncRNA


#### **Table 1.**

*Classification of ncRNAs.*

regulate gene expression through epigenetic, transcriptional and post-transcriptional mechanisms, and include microRNA (miRNA), tRNA-derived small RNA (tsRNA), piwi-interacting RNA (piRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) [4].

This chapter will focus on two classes of ncRNA, miRNA and tsRNA, which are highly enriched in the central nervous system (CNS) with important roles in neuronal function and dysfunction. The central roles played by these classes of ncRNAs and their dysregulation in disease, particularly their ability to regulate multiple genes, place them as promising biomarkers and therapeutic targets, entering many clinical trials.
