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Modeling AP2M1 developmental and epileptic encephalopathy in Drosophila.
Robin A Karge1, Florian P Fischer1, Hannah Schüth1
1Section of Epileptology, Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany.
Disease Models & Mechanisms
|September 29, 2025
Summary
Genetic defects in AP2M1 cause developmental and epileptic encephalopathy (DEE). Drosophila models revealed heat-sensitive paralysis and unexpected seizure resistance, suggesting neuronal development defects, not synaptic issues, underlie DEE.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- AP2M1 gene mutations cause developmental and epileptic encephalopathy (DEE).
- AP2M1 encodes the μ-subunit of adaptor protein complex 2 (AP-2), crucial for clathrin-mediated endocytosis.
- Understanding DEE mechanisms requires robust model systems.
Purpose of the Study:
- To model AP2M1-related DEE in Drosophila melanogaster.
- To investigate the underlying disease mechanisms of AP2M1-DEE.
- To explore the role of AP-2µ in neuronal function and seizure susceptibility.
Main Methods:
- Generated Drosophila models using RNA interference and CRISPR gene editing targeting the AP2M1 ortholog.
- Assessed neuronal morphology and function, including heat-sensitive paralysis and seizure susceptibility.
- Examined the effects of a specific human disease variant (p.Arg170Trp).
Main Results:
- Pan-neuronal knockdown of AP-2µ caused heat-sensitive paralysis and altered dendritic morphology.
- Affected flies exhibited resistance to antiseizure medications and reduced susceptibility to induced seizures.
- A CRISPR-engineered fly line with the p.Arg170Trp variant showed a milder, seizure-resistant phenotype.
Conclusions:
- Drosophila models of AP2M1-DEE display phenotypes contrasting with human presentation but consistent with other endocytosis-related genes.
- Hyperexcitability and seizures in AP2M1-DEE may arise from widespread neuronal development defects.
- Findings suggest a re-evaluation of direct synaptic dysfunction as the primary cause of seizures in AP2M1-DEE.
