Silencing of miR20a Is Crucial for Ngn1-Mediated Neuroprotection in Injured Spinal Cord

Laboratory of Stem Cell Biology, Department of Biotechnology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
Human gene therapy (Impact Factor: 3.76). 12/2011; 23(5):508-20. DOI: 10.1089/hum.2011.121
Source: PubMed


MicroRNAs (miRNAs) compose a relatively new discipline in biomedical research, and many physiological processes in disease have been associated with changes in miRNA expression. Several studies report that miRNAs participate in biological processes such as the control of secondary injury in several disease models. Recently, we identified novel miRNAs that were abnormally up-regulated in a traumatic spinal cord injury (SCI). In the current study, we focused on miR20a, which causes continuing motor neuron degeneration when overexpressed in SCI lesions. Blocking miR20a in SCI animals led to neural cell survival and eventual neurogenesis with rescued expression of the key target gene, neurogenin 1 (Ngn1). Infusion of siNgn1 resulted in functional deficit in the hindlimbs caused by aggressive secondary injury and actively enhanced the inflammation involved in secondary injury progression. The events involving miR20a underlie motor neuron and myelin destruction and pathophysiology and ultimately block regeneration in injured spinal cords. Inhibition of miR20a expression effectively induced definitive motor neuron survival and neurogenesis, and SCI animals showed improved functional deficit. In this study, we showed that abnormal expression of miR20a induces secondary injury, which suggests that miR20a could be a potential target for therapeutic intervention following SCI.

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    • "Up-regulating or down-regulating the expression of major target genes may exert similar effects as inhibition of miRNAs 15. "
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    ABSTRACT: microRNAs (miRNAs) are a novel class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. miRNAs can modulate gene expression and thus play important roles in diverse neurobiological processes, such as cell differentiation, growth, proliferation and neural activity, as well as the pathogenic processes of spinal cord injury (SCI) like inflammation, oxidation, demyelination and apoptosis. Results from animal studies have revealed the temporal alterations in the expression of a large set of miRNAs following SCI in adult rats, and the expressional changes in miRNAs following SCI is bidirectional (increase or decrease). In addition, several miRNAs have distinct roles in prognosis of SCI (protective, detrimental and varied). Taken together, the existing evidence suggests that abnormal miRNA expression following SCI contributes to the pathogenesis of SCI, and miRNAs may become potential targets for the therapy of SCI.
    Preview · Article · Sep 2014 · International journal of biological sciences
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    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.
    No preview · Article · Apr 2013 · Nature Reviews Neurology
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    ABSTRACT: The mammalian genome is replete with various classes of non-coding (nc) RNA genes. Many of them actively transcribe, and their relevance to CNS diseases is just beginning to be understood. CNS is one of the organs in the body that shows very high ncRNAs activity. Recent studies demonstrated that cerebral ischemia rapidly changes the expression profiles of different classes of ncRNAs: including microRNA, long noncoding RNA and piwi-interacting RNA. Several studies further showed that post-ischemic neuronal death and/or plasticity/regeneration can be altered by modulating specific microRNAs. These studies are of interest for therapeutic development as they may contribute to identifying new ncRNA targets that can be modulated to prevent secondary brain damage after stroke.
    No preview · Article · Aug 2013 · Neurochemistry International
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