Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice
Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice
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DOI：
10.1093/hmg/ddg267
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Lin, CLG
中科院分区：
文献类型：
--
作者：
Guo, H;Lai, LC;Lin, CLG
神经胶质谷氨酸转运体EAAT 2主要负责从突触间隙清除谷氨酸，并且先前已经报道了肌萎缩侧索硬化症（ALS）和阿尔茨海默病中EAAT 2的丢失。功能性EAAT 2的丧失可导致细胞外谷氨酸的积累，导致称为兴奋性毒性的细胞死亡。然而，它是否是导致神经元变性的级联反应中的主要原因还是细胞死亡的次要事件仍然是未知的。本研究的目的是产生过表达EAAT 2的转基因小鼠，然后将这些小鼠与ALS相关的突变SOD 1（G93 A）小鼠杂交，以研究补充EAAT 2的缺失是否会延迟或挽救疾病进展。我们表明，EAAT 2蛋白的量和相关的Na+依赖性谷氨酸摄取增加约2倍，在我们的EAAT 2转基因小鼠。转基因EAAT 2蛋白被适当地定位于细胞质膜上的细胞表面。EAAT 2表达增加保护神经元免受L-谷氨酸诱导的细胞毒性和体外细胞死亡。此外，我们的EAAT 2/G93 A双转基因小鼠与G93 A同窝小鼠相比，在握力下降方面表现出统计学显著（14天）延迟，但在瘫痪发作、体重下降或寿命方面没有表现出统计学显著（14天）延迟。此外，还观察到运动神经元及其轴突形态的损失以及包括半胱天冬酶-3活化和SOD 1聚集的其他事件的延迟。这些结果表明，EAAT 2的损失可能有助于，但不会导致ALS中的运动神经元变性。
The glial glutamate transporter EAAT2 is primarily responsible for clearance of glutamate from the synaptic cleft and loss of EAAT2 has been previously reported in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The loss of functional EAAT2 could lead to the accumulation of extracellular glutamate, resulting in cell death known as excitotoxicity. However, it is still unknown whether it is a primary cause in the cascade leading to neuron degeneration or a secondary event to cell death. The goals of this study were to generate transgenic mice overexpressing EAAT2 and then to cross these mice with the ALS-associated mutant SOD1(G93A) mice to investigate whether supplementation of the loss of EAAT2 would delay or rescue the disease progression. We show that the amount of EAAT2 protein and the associated Na+-dependent glutamate uptake was increased about 2-fold in our EAAT2 transgenic mice. The transgenic EAAT2 protein was properly localized to the cell surface on the plasma membrane. Increased EAAT2 expression protects neurons from L-glutamate induced cytotoxicity and cell death in vitro. Furthermore, our EAAT2/G93A double transgenic mice showed a statistically significant (14 days) delay in grip strength decline but not in the onset of paralysis, body weight decline or life span when compared with G93A littermates. Moreover, a delay in the loss of motor neurons and their axonal morphologies as well as other events including caspase-3 activation and SOD1 aggregation were also observed. These results suggest that the loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.