Modeling AP2M1 Developmental and Epileptic Encephalopathy in Drosophila

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.; Wolking, S.

doi:10.1101/2025.04.11.648441

bioRxiv · 10.1101/2025.04.11.648441

Modeling AP2M1 Developmental and Epileptic Encephalopathy in Drosophila

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.·Wolking, S.

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Abstract

Genetic defects in AP2M1, which encodes the -subunit of the adaptor protein complex 2 (AP-2) essential for clathrin-mediated endocytosis (CME), 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 knock-down of the Drosophila AP2M1 ortholog, AP-2{micro}, resulted in a consistent heat-sensitive paralysis phenotype and altered morphology in class IV dendritic arborization (c4da) neurons. Unexpectedly, affected flies were resistant to antiseizure medications and exhibited increased resistance to electrically induced seizures. A CRISPR-engineered fly line carrying the recurrent human disease variant p.Arg170Trp displayed a milder seizure resistance phenotype. While these findings contrast with the human phenotype, they align with previous studies on other CME-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.

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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., Wolking, S.. 2025-04-14. Modeling AP2M1 Developmental and Epileptic Encephalopathy in Drosophila. https://doi.org/10.1101/2025.04.11.648441

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