Era of the tiny titans: microRNAs

Authors

  • Sugunavathi Sepramaniam,

    1. Department of Biochemistry and Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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  • Kandiah Jeyaseelan

    Corresponding author
    1. Department of Biochemistry and Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    2. Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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The discovery of non-coding RNAs demonstrating regulatory control over gene expression has contravened the central dogma theory. Once considered as junk, these RNAs are now an area of active research. The ∼22 nucleotides long microRNAs (miRNAs), a subset of short non-coding RNAs, were the first to be considered attractive, and over the past decade they have been aggressively studied for roles in disease pathology as well as their relevance in therapeutics. As appropriate expression of miRNAs is critical for normal development, it is understandable that their dysregulation may be the cause or effect of a pathological condition. Madathil et al. [1] highlighted that: Although the change in miRNA expression in response to brain injury indicates their crucial roles and makes them ideal for therapeutic interventions, their precise function is still elusive. To date, there are still limitations regarding a targeted therapeutic intervention, given the ‘one miRNA and multiple targets’ phenomenon. Yet this very characteristic of miRNAs is also believed to be its forte, as it allows coordinated control of the many but related targets to bring about the desired outcomes. Although a miRNA-based targeted therapeutic intervention for central nervous system (CNS) injuries remains to be investigated, research into areas such as viral infection, heart disease and cancer have far advanced their discoveries into clinical trials, thus signifying the immense potential that these tiny oligonucleotides hold. Nonetheless, as emphasized by Madathil et al. [1], it is inevitable that a single alteration in miRNA expression will induce a cascade of changes in protein expression which will eventually impact on multiple signaling pathways. This was reinforced in our recent study where anti-miR-320a mediated recovery from acute stroke was evident with connotations in multiple crucial pathways [2]. Although the study proved that brain water channels, aquaporins 1 and 4, were direct targets of miR-320 and suppressing its expression would have implications in edema accumulation, it also identified a plethora of other potential targets with relevance to processes such as survival, proliferation, cell communication, transcriptional regulation and anti-inflammation. The radical reduction of ischemic damage seen by regulating miR-320 expression proposes it to be a potential therapeutic target for stroke. Nevertheless, due to the complexity imposed by the very promiscuous nature of miRNAs, it is critical to carefully access their clinical potential.

More recently, miR-137, -181c, -9 and -29a/b have been identified as non-invasive biomarkers of Alzheimer's disease where the expression of circulating miR-181c was reduced in serum samples of Alzheimer's patients [3]. Yet another report pronounced that expression of miR-181 cluster is down regulated in the penumbra upon ischemic brain injury [4]. These studies corroborate Madathil et al.'s hypothesis that alterations in miRNAs, upon any form of acute CNS injury, may contribute to the subsequent development of chronic brain diseases. Thus therapeutic strategies aimed at regulating crucial ‘acute injury response’ miRNAs may be able to halt the advancement of acute injury pathology into the development of chronic brain diseases. While the predisposition to age-related neurodegenerative diseases as a consequence of acute brain injury has been implicated previously, a more exhaustive study showed that upsurge in neuro-inflammation and subdual of neurogenesis, were the fundamental causes for progressive deterioration of the injured brain [5]. Thus focusing on the associated signaling pathways and relating them to subsequent processes could enable elucidation of important miRNAs in CNS injury.

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