Alterations in energy production in a Drosophila model for the X-linked dystonia-parkinsonism-related Taf1 deficiency

Background: gene, containing a hexanucleotide, the length of which is correlated to the severity of the disease. The SVA insertion moderately disrupts gene expression; however, the underlying disease mechanism remains enigmatic. Methods: Here, we characterized a fly model for Taf1 deficiency and performed a pilot RNA sequencing analysis. Subsequently, we validated these findings in Taf1-deficient flies and in XDP patient-derived fibroblasts. Results: We identified an upregulation of genes involved in lipid-dependent energy production as a compensatory mechanism to maintain proper ATP levels. However, studies in XDP patient-derived fibroblasts with minor TAF1 reduction did not confirm these findings. Conclusion: -oxidation is elevated in flies with severe TAF1 reduction but not detected in XDP-patient fibroblasts, suggesting that this compensatory mechanism may only manifest above a critical TAF1 dosage threshold, absent in patient basal conditions. This finding thus suggests that dosage-dependent metabolic responses occur following TAF1 loss.