Understanding Alcoholism Through microRNA Signatures in Brains of Human Alcoholics

Abstract

Advances in the fields of genomics and genetics in the last decade have identified a large number of genes that can potentially influence alcohol-drinking behavior in humans as well as animal models. Consequently, the task of identifying efficient molecular targets that could be used to develop effective therapeutics against the disease has become increasingly daunting. One of the reasons for this is the fact that each of the many alcohol-responsive genes only contributes a small effect to the overall mechanism and disease phenotype, as is characteristic of complex traits. Current research trends are hence shifting toward the analysis of gene networks rather than emphasizing individual genes. The discovery of microRNAs and their mechanisms of action on regulation of transcript level and protein translation have made evident the utility of these small non-coding RNA molecules that act as central coordinators of multiple cross-communicating cellular pathways. Cells exploit the fact that a single microRNA can target hundreds of mRNA transcripts and that a single mRNA transcript can be simultaneously targeted by distinct microRNAs, to ensure fine-tuned and/or redundant control over a large number of cellular functions. By the same token, we can use these properties of microRNAs to develop novel, targeted strategies to combat complex disorders. In this review, we will focus on recent discoveries of microRNA signatures in brain of human alcoholics supporting the hypothesis that changes in gene expression and regulation by microRNAs are responsible for long-term neuroadaptations occurring during development of alcoholism. We also discuss insights into the potential modulation of epigenetic regulators by a subset of microRNAs. Taken together, microRNA activity may be controlling many of the cellular mechanisms already known to be involved in the development of alcoholism, and suggests potential targets for the development of novel therapeutic interventions.

Stress‐Related Alcohol Consumption in Heavy Drinkers Correlates with Expression of miR‐10a, miR‐21, and Components of the TAR‐RNA‐Binding Protein‐Associated Complex

“…Given the well-known association between stress and risk for addiction, it is perhaps not surprising that changes in miRNA expression have also been proposed to play a role in risk for addiction to various substances (Hollander et al, 2010), including alcohol (Nunez and Mayfield, 2012). miR9 has been reported to play a key role in the development of alcohol tolerance by down- regulating the alpha subunit of BK channel, a high conductance calcium- and voltage-dependent potassium channel (Pietrzykowski et al, 2008).…”

Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

“…They are highly abundant in brain and mediate multiple biological processes, including brain development (Krichevsky, King, Donahue, Khrapko, & Kosik, 2003), synapse formation (Schratt et al, 2006), synaptic plasticity (Cohen, Lee, Chen, Li, & Fields, 2011; Smalheiser & Lugli, 2009), and neuroimmune signaling (Soreq & Wolf, 2011). miRNAs are capable of eliciting targeted actions in innate immunity- and epigenetic-related functions in glial cells (Nunez & Mayfield, 2012) and have been associated with development of the immune system and regulation of multiple immune functions (O’Neill, Sheedy, & McCoy, 2011). Also, TLR signaling can modulate miRNA expression via NF-κB regulation (Taganov, Boldin, Chang, & Baltimore, 2006).…”

“…Many miRNAs are altered in brains from human alcoholics (Lewohl et al, 2011) and ethanol-treated mice (Nunez et al, 2013), and many are predicted to target neuroimmune processes. Figure 2.3 depicts a model of neuroinflammatory miRNA signaling based on evidence from human alcoholics (Nunez & Mayfield, 2012). …”

“…microRNAs that target epige-netic factors are also activated to control and/or fine tune the ongoing remodeling of the cellular epigenome, allowing for long-term homeostatic and cellular adaptations. Figure and legend are from Nunez and Mayfield (2012).…”

Alteration of the miRNA expression profile in male porcine anterior pituitary cells in response to GHRH and CST and analysis of the potential roles for miRNAs in regulating GH

“…4, all details are listed in Table A.3). It is believed that a single miRNA targets hundreds of mRNA transcripts and a single mRNA transcript is simultaneously targeted by distinct miRNAs, to ensure fine-tuned and/or redundant control over a large number of cellular functions [29]. Bioinformatics targets of these miRNAs were then graphed using cytoscape to show the interactions between GH-associated miRNAs and their potential mRNA targets (Fig.…”