Karge, R.A., Fischer, F.P., Schüth, H., Wechner, A., Peter, S., Kilo, L.A., Dichter, M., Voigt, A., Tavosanis, G., van Loo, K.M.J., Koch, H., Weber, Y.G., Wolking, S. (2025). Modeling AP2M1 developmental and epileptic encephalopathy in Drosophila.  Dis. Model Mech. 18(11): dmm052419.

FBrf0263919

Research paper

Genetic defects in AP2M1, which encodes the μ-subunit of the adaptor protein complex 2 (AP-2) essential for clathrin-mediated endocytosis, cause a rare form of developmental and epileptic encephalopathy (DEE). In this study, we modeled AP2M1-DEE in Drosophila melanogaster to gain deeper insights into the underlying disease mechanisms. Pan-neuronal RNA interference against the Drosophila AP2M1 ortholog, AP-2µ, resulted in a consistent heat-sensitive paralysis phenotype and altered morphology in class IV dendritic arborization neurons. Unexpectedly, affected flies were resistant to antiseizure medications and exhibited decreased susceptibility to electrically induced seizures. A CRISPR-engineered fly line carrying the recurrent human disease variant p.Arg170Trp displayed a milder, seizure-resistant phenotype. Although these findings contrast with the human phenotype, they align with previous studies on other clathrin-mediated endocytosis-related genes in Drosophila. Our results suggest that hyperexcitability and seizures in AP2M1-DEE may stem from broader defects in neuronal development rather than direct synaptic dysfunction.