果蝇AP2M1发育性和癫痫性脑病的建模。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Robin A Karge, Florian P Fischer, Hannah Schüth, Aileen Wechner, Sabrina Peter, Lukas Kilo, Mato Dichter, Aaron Voigt, Gaia Tavosanis, Karen M J van Loo, Henner Koch, Yvonne G Weber, Stefan Wolking
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引用次数: 0

摘要

编码衔接蛋白复合物2 (AP-2)的μ亚基的AP2M1基因的遗传缺陷导致一种罕见的发育性和癫痫性脑病(DEE)。衔接蛋白复合物2 (AP-2)是网格蛋白介导的内吞作用(CME)所必需的。在这项研究中,我们模拟了黑腹果蝇的AP2M1-DEE,以深入了解潜在的疾病机制。针对果蝇AP2M1同源物AP-2µ的泛神经元RNA干扰(RNAi)导致了一致的热敏性麻痹表型和IV类树突状乔木(c4da)神经元的形态改变。出乎意料的是,受影响的果蝇对抗癫痫药物有抵抗力,并且对电诱发癫痫的易感性降低。携带复发性人类疾病变体p.a g170trp的crispr工程蝇系显示出较轻的抗癫痫表型。虽然这些发现与人类表型相反,但它们与之前对果蝇中其他cme相关基因的研究一致。我们的研究结果表明AP2M1-DEE的高兴奋性和癫痫发作可能源于更广泛的神经元发育缺陷,而不是直接的突触功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Modeling AP2M1 developmental and epileptic encephalopathy in drosophila.

Genetic defects in AP2M1, which encodes the μ-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 RNA interference (RNAi) against the Drosophila AP2M1 ortholog, AP-2µ, 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 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. 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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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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