Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders

Abstract

Non-coding RNAs (ncRNAs) have emerged as critical regulators of transcription, epigenetic processes, and gene silencing, which make them ideal candidates for insight into molecular evolution and a better understanding of the molecular pathways of neuropsychiatric disease. Here, we provide an overview of the current state of knowledge regarding various classes of ncRNAs and their role in neural plasticity and cognitive function, and highlight the potential contribution they may make to the development of a variety of neuropsychiatric disorders, including schizophrenia, addiction, and fear-related anxiety disorders.

Keywords: addiction; anxiety; neuropsychiatric disorder; non-coding RNA.

FIGURE 1

(A)miRNA biogenesis begins in the nucleus where Drosha and DGCR8 cleave the primary RNA resulting in a miRNA precursor that is exported to the cytoplasm by Exportin5 and Ran-GTP61 where it is then processed by Dicer and TRBP. Next, the mature miRNA duplex is incorporated to the RISC where it is cleaved Dicer, associates with AGO2, and subsequently binds to the 3′ UTR of a target RNA leading to either mRNA degradation or translational repression. (B) Similarly, siRNA biogenesis depends on Dicer activity and incorporation into the RISC, however siRNAs avoid cleavage by Drosha as they are derived from exogenous viral or endogenous double-stranded RNA molecules mostly within the cytoplasm. Given the specificity of base pairing, the final outcome of the siRNA interference is the cleavage and degradation of their target mRNAs.

FIGURE 2

Primary single-stranded intergenic piRNAs are transcribed within the nucleus from well-conserved clusters of repetitive elements. Once in the cytoplasm they either interact with MIWI proteins and initiate the “primary pathway,” or directly with MILI proteins to trigger the “ping-pong cycle.” PiRNAs associated with MILI direct its slicer activity against target mRNAs, thereby producing a secondary piRNA, which is then coupled to MIWI2. MIWI2 piRNA can return to the nucleus where it targets repetitive elements, or remains within the cytoplasm where it exerts endonuclease activity on the opposite strand to reproduce a new pre-piRNA that interacts with MILI in a self-amplification loop.

FIGURE 3

(A) Upon receiving a signal for DNA damage, the long ncRNA CCND1 binds to the TLS protein to direct a protein complex to the CCND1 target gene where allosteric modification of CREB and the histone acetyltranserases (HATs) CBP and p300 are produced, which results in gene silencing. (B) Long ncRNA Evf2 is transcribed from an ultra conserved intergenic region within the Dlx-5/6 locus. Binding of this long ncRNA to the Dlx-2 protein triggers transcriptional activation of the Dlx-5/6 enhancer region in a homeodomain-specific manner.