AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in neurodevelopmental disorders.
AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in neurodevelopmental disorders.
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DOI：
10.1242/dmm.049838
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发表时间：
2023-09-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
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作者：
AGAP 1是一种Arf 1 GTP酶激活蛋白，调节内溶酶体运输。破坏性变异与脑瘫和自闭症有关。我们报告了三个新的情况下，个人有微缺失变异AGAP 1。其中智力障碍3例，孤独症3例，肌张力障碍伴轴性肌张力减退1例，脑发育异常1例，生长障碍2例，面部畸形2例。我们使用果蝇直系同源基因CenG 1a研究了AGAP 1变体介导的神经发育障碍的潜在机制。我们发现，与对照组相比，轴突终末尺寸减小，神经元内体丰度增加，自噬增加。考虑到潜在的不完全突变，我们评估了基因-环境相互作用。我们发现整合应激反应蛋白eIF 2 α（或eIF 2A）的磷酸化水平基础升高，并且无法在随后的细胞毒性应激源下进一步增加eIF 2 α的磷酸化。CenG 1a突变果蝇暴露于环境损害后的致死率增加。我们提出了一种模型，其中AGAP 1功能的破坏损害了内溶酶体运输，长期激活综合应激反应，并使AGAP 1缺陷的细胞容易受到各种二次打击细胞毒性应激。该模型可能具有更广泛的适用性超越AGAP 1的情况下，遗传和环境的侮辱共同发生在个人与神经发育障碍。总结：AGAP 1缺失变体在三个神经发育障碍的个体中被鉴定，并且，使用功能丧失的果蝇模型，我们表明AGAP 1破坏损害神经元内溶酶体运输并长期激活应激反应。
AGAP1 is an Arf1 GTPase-activating protein that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report three new cases in which individuals had microdeletion variants in AGAP1. The affected individuals had intellectual disability (3/3), autism (3/3), dystonia with axial hypotonia (1/3), abnormalities of brain maturation (1/3), growth impairment (2/3) and facial dysmorphism (2/3). We investigated mechanisms potentially underlying AGAP1 variant-mediated neurodevelopmental impairments using the Drosophila ortholog CenG1a. We discovered reduced axon terminal size, increased neuronal endosome abundance and elevated autophagy compared to those in controls. Given potential incomplete penetrance, we assessed gene–environment interactions. We found basal elevation in the phosphorylation of the integrated stress-response protein eIF2α (or eIF2A) and inability to further increase eIF2α phosphorylation with subsequent cytotoxic stressors. CenG1a-mutant flies had increased lethality from exposure to environmental insults. We propose a model wherein disruption of AGAP1 function impairs endolysosomal trafficking, chronically activating the integrated stress response and leaving AGAP1-deficient cells susceptible to a variety of second-hit cytotoxic stressors. This model may have broader applicability beyond AGAP1 in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders. Summary: AGAP1 deletion variants were identified in three individuals with neurodevelopmental disorders, and, using a loss-of-function Drosophila model, we show that AGAP1 disruption impairs neuronal endolysosomal trafficking and chronically activates the stress response.
影响因子：
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作者：
Jacomin AC;Fauvarque MO;Taillebourg E
通讯作者：
Taillebourg E
影响因子：
3.7
作者：
Gündner AL;Hahn I;Sendscheid O;Aberle H;Hoch M
通讯作者：
Hoch M