Effects of Gallic Acid on Sleep and Circadian Rhythm in a Drosophila melanogaster Model of Fragile X Syndrome: An Integrative Behavioral and Bioinformatic Approach for Target Predictions.

Sleep and circadian rhythm (CR) disturbances are hallmark features of fragile X syndrome (FXS), a rare genetic disorder caused by a full mutation of the FMR1 gene, resulting in reduced or absent FMR1 protein (FMRP). Despite the clear genetic etiology, targeted treatment for FXS remains unavailable. Natural polyphenol gallic acid (GA) has great potential to modulate neurobiological effects and is attracting increased pharmacological interest due to its low toxicity and capacity to modulate neuronal signaling. Therefore, this study aimed to investigate the effects of GA on sleep and CR in the Drosophila melanogaster model of FXS and to further explore and propose potential gene and protein targets using a bioinformatic approach. GA effects on sleep and CR in seven different concentrations (100-1000 µM) were evaluated in dFmr1B55 mutants through high-resolution video monitoring. Bioinformatic analysis included protein-protein interaction and functional enrichment analysis linking the dFmr1 gene with GA. Behavioral results demonstrated that GA significantly modulates sleep and CR parameters in the fruit fly model of FXS in a concentration-dependent manner, with the most pronounced effect noticed at the lower tested concentration. Bioinformatic findings suggest that these effects may be mediated through the regulation of genes and proteins, including Rac1, bsk, Jra, Cyfip, and Dscam1, which are functionally connected to dFmr1 and implicated in sleep and CR processes. These results provide novel insights and preliminary findings into the potential of GA to ameliorate sleep and CR disturbances in the fruit fly model of FXS, offering a framework for future experimental validation.