Long Non-Coding RNAs: The New Frontier into Understanding the Etiology of Alcohol Use Disorder

Abstract

Alcohol use disorder (AUD) is a complex, chronic, debilitating condition impacting millions worldwide. Genetic, environmental, and epigenetic factors are known to contribute to the development of AUD. Long non-coding RNAs (lncRNAs) are a class of regulatory RNAs, commonly referred to as the “dark matter” of the genome, with little to no protein-coding potential. LncRNAs have been implicated in numerous processes critical for cell survival, suggesting that they play important functional roles in regulating different cell processes. LncRNAs were also shown to display higher tissue specificity than protein-coding genes and have a higher abundance in the brain and central nervous system, demonstrating a possible role in the etiology of psychiatric disorders. Indeed, genetic (e.g., genome-wide association studies (GWAS)), molecular (e.g., expression quantitative trait loci (eQTL)) and epigenetic studies from postmortem brain tissues have identified a growing list of lncRNAs associated with neuropsychiatric and substance use disorders. Given that the expression patterns of lncRNAs have been associated with widespread changes in the transcriptome, including methylation, chromatin architecture, and activation or suppression of translational activity, the regulatory nature of lncRNAs may be ubiquitous and an innate component of gene regulation. In this review, we present a synopsis of the functional impact that lncRNAs may play in the etiology of AUD. We also discuss the classifications of lncRNAs, their known functional roles, and therapeutic advancements in the field of lncRNAs to further clarify the functional relationship between lncRNAs and AUD.

Mutation of novel ethanol‐responsive lncRNAGm41261 impacts ethanol‐related behavioral responses in mice

“…This study adds to a small but growing list of lncRNAs that are implicated in mediating ethanol's effects on the brain, ethanol-related behavioral responses and AUD. 21,32,76 As individual RNAs are rapidly emerging as highly selec-…”

“…This study adds to a small but growing list of lncRNAs that are implicated in mediating ethanol's effects on the brain, ethanol‐related behavioral responses and AUD. 21 , 32 , 76 As individual RNAs are rapidly emerging as highly selective and efficacious therapeutic targets for small molecule drugs (for reviews, see References 77 , 78 ), we propose that the ethanol‐responsive lncRNA transcriptome is an expansive, untapped resource for future development of novel AUD therapeutics.…”

Problematic alcohol use: A relational illness

“…Neuropathological theories highlight the role of physiological and biochemical factors (Erdozain et al., 2014). Environmental factors such as adverse childhood experiences (Felitti et al., 1998) and adverse life events (Sartor et al., 2014) are also correlated with PAU, as well as epigenetic factors shown to play a role in the expression of genes with stress and external experiences (Denham et al., 2022). Biopsychosocial (Skewes & Gonzalez, 2013) and neuropsychological (Kwako et al., 2019) theories have also been proposed.…”

The Role of miR-128 in Neurodegenerative Diseases

“…Indeed, in recent years, ncRNAs have become key molecules implicated in almost every process leading to the onset and progression of NDDs. The association between ncRNAs and disease pathogenesis has also been suggested in Parkinson’s disease (PD) [ 11 ], Huntington’s disease (HD) [ 12 ], Alzheimer’s disease (AD) [ 13 ], and other neurodegenerative disorders [ 14 ]. Overall, six major ncRNA-mediated mechanisms are likely to contribute to the neurodegenerative process: epigenetic regulation, regulation of gene expression by RNA interference (RNAi), alternative splicing, mRNA stability, translation regulation, and molecular snare [ 15 ].…”