ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
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DOI：
10.1172/jci79990
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发表时间：
2019-05-01
影响因子：
15.9
通讯作者：
Groszer, Matthias
中科院分区：
文献类型：
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作者：
Hirose, Takuo;Cabrera-Socorro, Alfredo;Groszer, Matthias
胞浆H+-ATP酶依赖性（V-ATP酶依赖性）功能对于神经蛋白质稳态是关键的，并且参与神经变性和脑肿瘤发生。我们确定了一个病人的暴发性神经变性的发育中的大脑携带从头剪接位点变异的ATP 6AP 2编码的V-ATP酶的辅助蛋白。来自该患者的诱导多能干细胞衍生的（iPSC衍生的）神经元的功能研究揭示了自发活动减少和溶酶体酸化和蛋白质降解的严重缺陷，导致神经元细胞死亡。这些缺陷可以通过表达全长ATP 6AP 2来解决。在发育中的小鼠脑中Atp 6ap 2的条件性缺失损害了V-ATP酶依赖性功能，导致神经干细胞自我更新受损、神经元过早分化和凋亡，导致几乎整个皮质的变性。体外研究表明，ATP 6AP 2缺陷会降低V-ATP酶膜组装并增加内体-溶酶体融合。我们的结论是，ATP 6AP 2是一个关键的调解人的V-ATP酶依赖的信号和蛋白质降解在发展中的人类中枢神经系统。
Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.