Collège de France, Center for Interdisciplinary Research in Biology, Paris, France.
INSERM, UMR-S 1270, Paris, France.
J Clin Invest. 2019 Apr 15;129(5):2145-2162. doi: 10.1172/JCI79990.
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.
液泡型 H+-ATP 酶依赖的（V-ATPase-dependent）功能对神经稳态至关重要，与神经退行性变和脑肿瘤发生有关。我们发现了一名患有进行性脑发育神经退行性疾病的患者，该患者携带编码 V-ATPase 辅助蛋白的 ATP6AP2 剪接位点变异。对该患者诱导多能干细胞衍生（iPSC 衍生）神经元的功能研究表明，自发性活动减少，溶酶体酸化和蛋白降解严重不足，导致神经元细胞死亡。这些缺陷可以通过表达全长 ATP6AP2 得到挽救。在发育中的小鼠大脑中条件性敲除 Atp6ap2 会损害 V-ATPase 依赖的功能，导致神经干细胞自我更新受损、过早的神经元分化和凋亡，从而导致几乎整个皮质的退化。体外研究表明，ATP6AP2 缺乏会减少 V-ATPase 膜组装并增加内体-溶酶体融合。我们得出结论，ATP6AP2 是人类中枢神经系统中 V-ATPase 依赖的信号转导和蛋白降解的关键介质。
