The roles of FTO and m6A RNA methylation in alcohol use disorder

Alcohol use disorders (AUD) are a global health concern, and understanding their molecular mechanisms is crucial for targeted therapeutics. Recent genome-wide association studies (GWAS) implicated the FTO gene in AUD susceptibility.

The FTO gene encodes an enzyme responsible for demethylating N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, impacting various RNA species´ functions. However, the causal and functional roles of FTO and m6A RNA methylation in AUD remain unexplored.

Our innovative research aims to elucidate FTO and m6A RNA methylation´s roles in AUD using (i) animal (rat) models of alcohol dependence, (ii) neuronal cell cultures exposed to alcohol, and (iii) human postmortem brain tissue from individuals with AUD. Our multidisciplinary approach bridges a critical knowledge gap in the field.

Preliminary results indicate a causal relationship between FTO and increased alcohol intake, while postmortem data reveal significant m6A RNA methylation changes in circular RNAs (circRNAs) within the amygdala of AUD patients. These findings suggest that the FTO-m6A-circRNA pathway may be a novel, targetable mechanism in AUD etiology.

In conclusion, our pioneering project aims to provide novel insights into m6A RNA methylation´s role in AUD, with the potential to significantly enhance our understanding of the disorder and contribute to the development of innovative, epitranscriptome-targeting therapeutics.