Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse
Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse
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DOI：
10.1038/nn1609
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发表时间：
2006-01-01
影响因子：
25
通讯作者：
Swanson, RA
中科院分区：
文献类型：
--
作者：
Aoyama, K;Suh, SW;Swanson, RA
神经递质谷氨酸的摄取主要由星形胶质细胞上表达的转运体来实现，这些转运体的下调会导致癫痫发作和神经元死亡。神经元也表达一种谷氨酸转运体，称为兴奋性氨基酸载体 - 1（EAAC1），但该转运体的生理功能仍不确定。在此我们报道，基因敲除EAAC1（Slc1a1（-/-））的小鼠神经元谷胱甘肽水平降低，并且随着年龄增长，出现脑萎缩和行为改变。EAAC1还能快速转运半胱氨酸，这是神经元合成谷胱甘肽必不可少的前体。发现EAAC1（-/-）小鼠海马切片中的神经元谷胱甘肽含量降低，氧化剂水平升高，对氧化损伤的敏感性增加。通过用一种可透过细胞膜的半胱氨酸前体N - 乙酰半胱氨酸治疗EAAC1（-/-）小鼠，这些变化得以逆转。这些发现表明，EAAC1是神经元摄取半胱氨酸的主要途径，并且EAAC1缺乏会导致神经元谷胱甘肽代谢受损、氧化应激和年龄相关性神经退行性变。
Uptake of the neurotransmitter glutamate is effected primarily by transporters expressed on astrocytes, and downregulation of these transporters leads to seizures and neuronal death. Neurons also express a glutamate transporter, termed excitatory amino acid carrier-1 (EAAC1), but the physiological function of this transporter remains uncertain. Here we report that genetically EAAC1-null (Slc1a1(-/-)) mice have reduced neuronal glutathione levels and, with aging, develop brain atrophy and behavioral changes. EAAC1 can also rapidly transport cysteine, an obligate precursor for neuronal glutathione synthesis. Neurons in the hippocampal slices of EAAC1(-/-) mice were found to have reduced glutathione content, increased oxidant levels and increased susceptibility to oxidant injury. These changes were reversed by treating the EAAC1(-/-) mice with N-acetylcysteine, a membrane-permeable cysteine precursor. These findings suggest that EAAC1 is the primary route for neuronal cysteine uptake and that EAAC1 deficiency thereby leads to impaired neuronal glutathione metabolism, oxidative stress and age-dependent neurodegeneration.