Non-Coding RNAs in Psychiatric Disorders and Suicidal Behavior

Abstract

It is well known that only a small proportion of the human genome code for proteins; the rest belong to the family of RNAs that do not code for protein and are known as non-coding RNAs (ncRNAs). ncRNAs are further divided into two subclasses based on size: 1) long non-coding RNAs (lncRNAs; >200 nucleotides) and 2) small RNAs (<200 nucleotides). Small RNAs contain various family members that include microRNAs (miRNAs), small interfering RNAs (siRNAs), piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and small nuclear RNAs (snRNAs). The roles of ncRNAs, especially lncRNAs and miRNAs, are well documented in brain development, homeostasis, stress responses, and neural plasticity. It has also been reported that ncRNAs can influence the development of psychiatric disorders including schizophrenia, major depressive disorder, and bipolar disorder. More recently, their roles are being investigated in suicidal behavior. In this article, we have comprehensively reviewed the findings of lncRNA and miRNA expression changes and their functions in various psychiatric disorders including suicidal behavior. We primarily focused on studies that have been done in postmortem human brain. In addition, we have briefly reviewed the role of other small RNAs (e.g. piwiRNA, siRNA, snRNA, and snoRNAs) and their expression changes in psychiatric illnesses.

Keywords: bipolar disorder; long non-coding RNAs; major depressive disorder; microRNAs; schizophrenia.

Figure 1

Long non-coding RNA biogenesis and functions. Long non-coding RNAs are transcribed by RNA polymerase II and are processed to mature RNA by the same method as protein-coding mRNAs as detailed in the text. The considerable functions of lncRNAs are: chromatin modification, transcriptional activation/suppression, sponge, and scaffold. The functions of lncRNAs depend on the type of lncRNAs. lncRNA, long non-coding RNA; RNP, ribonucleoprotein.

Figure 2

MiRNA biogenesis and functions. Primary miRNA is transcribed from encoded gene. RNase III enzyme Drosha generates precursor miRNA by removing the flanking segments and -11 bp stem region of pri-miRNA. Drosha requires DiGeorge syndrome critical region 8 (DGCR8) to complete this process. pre-miRNAs are then transported from nucleus to cytoplasm by a transporter Exportin-5 (XPO5) in a Ran-GTP-dependent manner. In the cytoplasm, Dicer converts pre-miRNA into double-strand mature miRNA. Dicer requires TAR RNA-binding protein (TRBP) as a cofactor. Finally, one strand of miRNA/miRNA* duplex loads onto Argonaute homolog protein (Ago) to make RNA-induced silencing complex (RISC). RISC/miRNA complex mainly works as suppressor of mRNA expression through translational blockage, transcript degradation, and deadenylation.

Figure 3

Schematic diagram of the non-coding RNAs’ impact on psychiatric illnesses and suicidality. Risk factors for mental illnesses include early life adversity, current or recurrent life events that along with gene environment interaction can lead to epigenetic modifications mediated by ncRNAs. These modifications can give rise to neuropathology mediated by changes at cellular and/or molecular levels, which can subsequently alter neural circuitry. Phenotypic changes can arise from circuitry changes that can mediate the development of psychiatric illnesses such as major depression, bipolar disorder and schizophrenia. Suicidal behavior could be a manifestation of psychiatric illnesses or may be independent of psychiatric illnesses. ncRNAs, non-coding RNA.