Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS)
Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS)
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DOI：
10.1073/pnas.032539299
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发表时间：
2002-02-05
影响因子：
11.1
通讯作者：
Rothstein, JD
中科院分区：
文献类型：
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作者：
Howland, DS;Liu, J;Rothstein, JD
在Sprague-Dawley大鼠中转基因过表达含有肌萎缩性侧索硬化症（ALS）相关家族基因突变（SOD1(G93A)）的CU+2/Zn+2超氧化物歧化酶1（SOD1）可导致ALS样运动神经元疾病。这些大鼠的运动神经元疾病依赖于高水平的SOD1突变表达，从幼年症状前大鼠脊髓内源性SOD1的8倍增加到终末期动物的16倍。这些大鼠发病较早，约为115天，此后疾病进展非常迅速，平均11天内达到终末期。病理异常包括最初出现在腰椎脊髓的空泡，随后出现在更多的颈椎区域，以及SOD1、Hsp70、神经丝和泛素染色的包涵体。在脊髓和脑干运动神经元死亡前，脊髓和脑干的空泡化和神经胶质瘤是明显的。脊髓前角EAAT2谷氨酸转运体的局灶性丧失与胶质细胞增生同时发生，但出现在运动神经元/轴突变性之前。在终末期疾病中，胶质瘤增加，腹角EAAT2丢失超过90%，表明该蛋白在导致ALS细胞死亡的事件中起作用。这些转基因大鼠为进行实验和治疗开发提供了宝贵的资源，目前用现有的ALS转基因小鼠很难或不可能进行。
Transgenic overexpression of CU+2/Zn+2 superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1(G93A)) in a Sprague-Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression, increasing from 8-fold over endogenous SOD1 in the spinal cord of young presymptomatic rats to 16-fold in end-stage animals. Disease onset in these rats was early, approximate to115 days, and disease progression was very rapid thereafter with affected rats reaching end stage on average within 11 days. Pathological abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas, along with inclusion bodies that stained for SOD1, Hsp70, neurofilaments, and ubiquitin. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate transporter in the ventral horn of the spinal cord coincided with gliosis, but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS. These transgenic rats provide a valuable resource to pursue experimentation and therapeutic development, currently difficult or impossible to perform with existing ALS transgenic mice.