Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice
Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice
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DOI：
10.1016/j.nbd.2011.12.016
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发表时间：
2012-03-01
影响因子：
6.1
通讯作者：
Nakaki, Toshio
中科院分区：
文献类型：
--
作者：
Aoyama, Koji;Wang, Fan;Nakaki, Toshio
谷胱甘肽（GSH）是大脑中重要的神经保护分子。增加神经元 GSH 水平的策略是治疗神经退行性疾病的一种有前途的方法。然而，促进神经元特异性 GSH 合成的调节机制仍然难以捉摸。谷氨酸转运蛋白相关蛋白 3-18 (GTRAP3-18) 是一种与兴奋性氨基酸载体 1 (EAAC1) 相互作用的内质网蛋白，EAAC1 是一种神经元谷氨酸/半胱氨酸转运蛋白。为了研究增加体内神经元 GSH 水平的潜在调节机制，我们使用基因靶向方法生成了 GTRAP3-18 缺陷 (GTRAP3-18(-/-)) 小鼠。 GTRAP3-18 基因的破坏导致质膜中 EAAC1 表达增加、神经元 GSH 含量增加以及针对氧化应激的神经保护作用。此外，GTRAP3-18(-/-) 小鼠在运动/空间学习和记忆测试中比野生型小鼠表现更好。因此，抑制 GTRAP3-18 通过增加 GSH 含量来增强神经元对氧化应激的抵抗力，并促进认知功能。目前的结果可能为神经退行性疾病治疗的开发提供分子基础。 (C) 2011 Elsevier Inc. 保留所有权利。
Glutathione (GSH) is an important neuroprotective molecule in the brain. The strategy to increase neuronal GSH level is a promising approach to the treatment of neurodegenerative diseases. However, the regulatory mechanism by which neuron-specific GSH synthesis is facilitated remains elusive. Glutamate transporter-associated protein 3-18 (GTRAP3-18) is an endoplasmic reticulum protein interacting with excitatory amino acid carrier 1 (EAAC1), which is a neuronal glutamate/cysteine transporter. To investigate the potential regulatory mechanism to increase neuronal GSH level in vivo, we generated GTRAP3-18-deficient (GTRAP3-18(-/-)) mice using a gene-targeting approach. Disruption of the GTRAP3-18 gene resulted in increased EAAC1 expression in the plasma membrane, increased neuronal GSH content and neuroprotection against oxidative stress. In addition, GTRAP3-18(-/-) mice performed better in motor/spatial learning and memory tests than wild-type mice. Therefore, the suppression of GTRAP3-18 increases neuronal resistance to oxidative stress by increasing GSH content and also facilitates cognitive function. The present results may provide a molecular basis for the development of treatments for neurodegenerative diseases. (C) 2011 Elsevier Inc. All rights reserved.