Year: 2025
Type: article
Abstract: 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.
Source: Disease Models & Mechanisms
DOI: 10.1242/dmm.052419
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,750
Awards: G1402406509, G1782776108, Treat-ION - Neue Therapien für neurologische Ionenkanal- und Transporterstörungen - Teilprojekt Register, Charakterisierung von Erkrankungs-assoziierten genetischen Regionen, Datenintegration und Clinical Decision Support System für die Präzisionstherapie, G3195815600, G3339823769, G336424259, G5375928257
OpenAlex ID: W4414614334