Small RNAs in Neurological Disorders

Abstract

Small RNAs (ribonucleic acids) are a group of noncoding RNA molecules with modulation functions that span a broad range, from RNA modification to protein synthesis regulation. The expression of small RNAs is found to be widespread in all eukaryotes, and more than a third of protein‐coding genes in the human genome are regulated by small RNAs. Mounting evidence suggests that the appropriate spatiotemporal expression of small RNAs, in particular microRNAs (miRNAs), is required for both brain morphogenesis and nervous system development. Moreover, dysregulation of specific miRNAs is possibly correlated with the pathogenesis of neurodevelopmental disorders. Understanding the potential roles of small regulatory RNAs in neural development and various human neurological disorders could reveal therapeutic applications that involve restoring or inhibiting the function of small RNAs.

Key Concepts:

  • Small RNAs have been found in all major groups of eukaryotes.

  • Small RNAs are divided into four classes: microRNAs, small interacting RNAs, Piwi‐interacting RNAs and small nucleolar RNAs.

  • In humans, microRNAs play important functional roles, interacting with at least 30% of all mRNAs.

  • MicroRNAs are highly involved not only in normal brain function, but also in many developmental disorders.

  • Known to act on mRNAs, microRNAs will degrade, translationally inhibit or even upregulate mRNA expression.

  • One microRNA can affect the course of several neurodevelopmental disorders.

  • A full understanding of microRNA function will yield possible medicinal treatments.

Keywords: microRNAs; Alzheimer disease; Parkinson disease; Huntington disease; fragile X syndrome; Rett syndrome; DiGeorge syndrome; Down syndrome; multiple sclerosis; spina bifida

Figure 1.

miRNA and siRNA biogenesis. miRNAs are initially transcribed from genomic DNA to long primary transcripts (pri‐miRNAs) that are capped and polyadenylated. The pri‐miRNAs are then processed by a Drosha/DGCR8 complex to yield stem–loop structures that are precursors of miRNAs (pre‐miRNAs). After pre‐miRNAs are transported to cytoplasm by Exportin5/RnaGTP, they undergo further processing by Dicer. One strand of the miRNA duplex is selectively loaded into the RNA‐induced silencing complex (RISC) and guides target transcripts by mRNA cleavage or translation repression. dsRNAs (dsRNAs) are cleaved via Dicer. These small RNAs are incorporated into the RISC, and the guide strand of the siRNA recognises target sites to direct mRNA cleavage.

Figure 2.

Ping‐pong model of piRNA production. Antisense primary piRNAs are generated from transposons and interact with Piwi/Aub. Piwi/Aub‐antisense piRNA complex binds to sense transcripts and directs their cleavage. Subsequently, the Piwi‐class Argonaute protein (Ago3) binds the resulting sense piRNA and directs the cleavage of target antisense transcripts, producing new antisense piRNAs.

Figure 3.

snoRNA assembly and transport. snoRNAs are synthesised within pre‐mRNA introns by exonucleolytic trimming. A single snoRNA molecule is then folded and assembled by four snoRNA core proteins to form snoRNA.

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Lin, Li, Vitale, Angela V, and Jin, Peng(Apr 2010) Small RNAs in Neurological Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022385]