The Angelman syndrome protein Ube3a/E6AP is required for Golgi acidification and surface protein sialylation.
The Angelman syndrome protein Ube3a/E6AP is required for Golgi acidification and surface protein sialylation.
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DOI：
10.1523/jneurosci.1930-11.2013
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发表时间：
2013-02-27
期刊：
影响因子：
--
通讯作者：
Ehlers MD
中科院分区：
文献类型：
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作者：
Condon KH;Ho J;Robinson CG;Hanus C;Ehlers MD
Angelman 综合征 (AS) 是一种严重的出生后大脑发育障碍，由 HECT（与 E6AP 羧基末端同源）结构域 E3 泛素连接酶 Ube3a/E6AP 神经元特异性缺失引起。尽管最近描述了 AS 小鼠模型中的突触和行为缺陷，但 Ube3a 的细胞作用仍然是个谜。尽管神经元特异性印记被认为可以将疾病限制在大脑中，但 Ube3a 却广泛表达，这表明它在细胞功能中发挥着更广泛的作用。在当前的研究中，我们证明了 AS (UBE3Am−/p+) 小鼠皮质中高尔基体 (GA) 的严重结构破坏和脑池肿胀。在 Ube3a 敲低细胞系和 UBE3Am−/p+ 皮质神经元中，GA 严重酸化不足，导致渗透性肿胀。在体外和体内，Ube3a 的缺失和相应的 GA pH 值升高与蛋白质唾液酸化的显着减少有关，这一过程高度依赖于腔内高尔基体 pH 值。 GA 离子稳态的改变可能提供了与 AS 相关的多种可塑性和神经发育缺陷的共同细胞病理生理学基础。
Angelman syndrome (AS) is a severe disorder of postnatal brain development caused by neuron-specific loss of the HECT (homologous to E6AP carboxy terminus) domain E3 ubiquitin ligase Ube3a/E6AP. The cellular role of Ube3a remains enigmatic despite recent descriptions of synaptic and behavioral deficits in AS mouse models. Although neuron-specific imprinting is thought to limit the disease to the brain, Ube3a is expressed ubiquitously, suggesting a broader role in cellular function. In the current study, we demonstrate a profound structural disruption and cisternal swelling of the Golgi apparatus (GA) in the cortex of AS (UBE3Am−/p+) mice. In Ube3a knockdown cell lines and UBE3Am−/p+ cortical neurons, the GA is severely under-acidified, leading to osmotic swelling. Both in vitro and in vivo, the loss of Ube3a and corresponding elevated pH of the GA is associated with a marked reduction in protein sialylation, a process highly dependent on intralumenal Golgi pH. Altered ion homeostasis of the GA may provide a common cellular pathophysiology underlying the diverse plasticity and neurodevelopmental deficits associated with AS.