The emerging roles of microRNAs in CNS injuries

Abstract

The consequences of injuries to the CNS are profound and persistent, resulting in substantial burden to both the individual patient and society. Existing treatments for CNS injuries such as stroke, traumatic brain injury and spinal cord injury have proved inadequate, partly owing to an incomplete understanding of post-injury cellular and molecular changes. MicroRNAs (miRNAs) are RNA molecules composed of 20-24 nucleotides that function to inhibit mRNA translation and have key roles in normal CNS development and function, as well as in disease. However, a role for miRNAs as effectors of CNS injury has recently emerged. Use of bioinformatics to assess the mRNA targets of miRNAs enables high-order analysis of interconnected networks, and can reveal affected pathways that may not be identifiable with the use of traditional techniques such as gene knock-in or knockout approaches, or mRNA microarrays. In this Review, we discuss the findings of miRNA microarray studies of spinal cord injury, traumatic brain injury and stroke, as well as the use of gene ontological algorithms to discern global patterns of molecular and cellular changes following such injuries. Furthermore, we examine the current state of miRNA-based therapies and their potential to improve functional outcomes in patients with CNS injuries.

Figure 1

Therapeutic modulation of miRNA activity. miRNA mimics are molecules that can be used to overexpress miRNAs (1). They contain modified cyclopentylguanine bases, which enable association with the RISC within the cytoplasm to inhibit mRNA translation. Pri-miRNAs and pre-miRNAs can be expressed within cells by a plasmid, and the transcript is then processed by endogenous enzymes into mature miRNA (2). 2′-O-methyl antagomiRs and LNAs inhibit miRNA function by binding to mature miRNAs, thereby preventing their interaction with target mRNAs (3). Plasmids encoding an miRNA sponge transcript can be used for stable miRNA inhibition (4). The sponge transcript contains repeats of complementary sequences to the target miRNA (red regions of transcript), thereby sequestering miRNAs away from endogenous targets. Exosomes are BBB-crossing lipid vesicles that can deliver either miRNA mimics or inhibitors to modulate miRNA activity (5). Solid arrows indicate pathways that lead to increased miRNA activity; dashed arrows indicate pathways that lead to inhibition of miRNA activity. Abbreviations: BBB, blood–brain barrier; LNA, locked nucleic acid; miRNA, microRNA; pre-miRNA, precursor miRNA; pri-miRNA, primary miRNA; RISC, RNA-induced silencing complex; TRBP, TAR RNA-binding protein.