The Emerging Impact of microRNAs in Neurotrauma Pathophysiology and Therapy

Excerpt

Neurotrauma results in significant morbidity and mortality, due in large part to the vast array of cellular changes occurring in the central nervous system (CNS). Elucidating the complex nature of such transformations is critical in understanding the resulting pathogenesis. MicroRNAs (miRNAs) are 20–24 nucleotide long RNA molecules that regulate cellular function epigenetically. As they are implicated in various CNS injuries, identifying how they are affected by neurotrauma can provide insight into the molecular networks regulating cellular responses. In this chapter, the diverse roles of miRNAs in stroke and traumatic brain injury (TBI) obtained from human and animal studies are explored. Their potential as biomarkers for the type and severity of injury is also considered. Finally, the promise of miRNA-based therapeutics in improving outcomes for stroke and TBI is discussed.

Neurotrauma, such as stroke and TBI, are common pathologies that affect more than 10 million people in the United States alone (Coronado et al., 2011; National Stroke Association, 2014). These diseases are a significant cause of morbidity and mortality, primarily because of a lack of effective diagnostic tools and therapies. A major impediment for successful outcomes is the incomplete understanding of mechanisms underpinning these pathologies because cellular and molecular changes are dynamic and complex. Therefore, it is imperative to develop sound insights into stroke and TBI pathogenesis.

Capturing a snapshot of the multitude of changes after injury can be accomplished by using microarrays to identify altered expression levels of the transcriptome (Munro and Perreau, 2009). These studies have shown that microRNAs (miRNAs) are as important as messenger RNAs (mRNAs) in regulating both central nervous system (CNS) homeostasis and pathology (Qureshi and Mehler, 2012; Salta and DeStrooper, 2012). miRNAs are a family of short noncoding RNAs (ncRNAs)—in contrast to long protein-coding mRNAs—that epigenetically regulate gene function by inhibiting mRNA translation (Carthew and Sontheimer, 2009). A single miRNA can antagonize numerous distinct mRNAs and, conversely, a single mRNA can be targeted by a number of different miRNAs. Because of these types of interactions, miRNAs are thought of as potent regulators of gene networks (Gurtan and Sharp, 2013), and have been implicated in neural development and disease (Bian and Sun, 2011; Meza-Sosa et al., 2012). Hence they have the potential to serve as important markers of as well as therapeutic for CNS injury.

In this chapter, the biogenesis of miRNAs and their roles in CNS development are summarized. Studies describing the changes and effects of miRNAs in patients with—and in animal models of—stroke and TBI as well as their implications for use as biomarkers and diagnostics tools are extensively discussed. Furthermore, common themes between these injuries are identified. Finally, the development and promise of miRNA-based therapies is highlighted.