Marked synergism between mutant SOD1 and glutamate transport inhibition in the induction of motor neuronal degeneration in spinal cord slice cultures.
Marked synergism between mutant SOD1 and glutamate transport inhibition in the induction of motor neuronal degeneration in spinal cord slice cultures.
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DOI：
10.1016/j.brainres.2012.02.005
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发表时间：
2012-04-11
期刊：
影响因子：
2.9
通讯作者：
Weiss JH
中科院分区：
文献类型：
--
作者：
Yin HZ;Weiss JH
ALS脊髓中星形胶质细胞谷氨酸转运能力的丧失支持对疾病中运动神经元（MN）损伤的兴奋性毒性贡献，并且Cu/Zn超氧化物歧化酶（SOD 1）中功能突变的显性获得导致某些家族形式的ALS。我们使用野生型和G93 A SOD 1突变大鼠脊髓的器官型切片培养物来研究兴奋性毒性和突变SOD 1在MN变性诱导中的存在之间的相互作用。从1周龄幼仔制备切片培养物，在体外再培养一周后，将一些幼仔暴露于低水平（30 µM）的谷氨酸摄取抑制剂反式吡咯烷-2，4-二羧酸（PDC）3周或更高水平（50 µM）48 h，然后进行组织化学标记以评估MN损伤。在野生型动物中，这些暴露导致相对较少的MN变性。类似地，在来自未暴露于PDC的SOD 1突变动物的切片中观察到很少的MN变性。然而，添加PDC SOD 1突变体切片导致大量的MN损伤，这是显着减弱钙渗透AMPA型（Ca-AMPA）谷氨酸通道阻滞剂，或一氧化氮合酶拮抗剂。这些观察结果说明了器官型培养模型的效用，用于调查ALS中MN变性的细胞内相互作用，并支持以下假设：MN上的Ca-AMPA通道的激活提供了代谢负荷，该代谢负荷与突变SOD 1在MN损伤诱导中的有害作用协同作用。
Loss of astrocytic glutamate transport capacity in ALS spinal cord supports an excitotoxic contribution to motor neuron (MN) damage in the disease, and dominant gain of function mutations in Cu/Zn superoxide dismutase (SOD1) cause certain familial forms of ALS. We have used organotypic slice cultures from wild type and G93A SOD1 mutant rat spinal cords to examine interactions between excitotoxicity and the presence of mutant SOD1 in the induction of MN degeneration. Slice cultures were prepared from 1 week old pups, and after an additional week in vitro, some were exposed to either a low level (30 µM) of the glutamate uptake inhibitor, trans-pyrrolidine-2,4-dicarboxylic acid (PDC) for 3 weeks, or a higher level (50 µM) for 48 h, followed by histochemical labeling to assess MN injury. In wild type animals these exposures caused relatively little MN degeneration. Similarly, little MN degeneration was seen in slices from SOD1 mutant animals that were not exposed to PDC. However, addtion of PDC to SOD1 mutant slices resulted in substantial MN injury, which was markedly attenuated by a Ca2+ permeable AMPA-type (Ca-AMPA) glutamate channel blocker, or by a nitric oxide synthase antagonist. These observations illustrate the utility of the organotypic culture model for the investigation of intracellular interactions underlying MN degeneration in ALS, and support the hypothesis that activation of Ca-AMPA channels on MNs provides a metabolic burden that synergizes with deleterious effects of mutant SOD1 in the induction of MN injury.
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影响因子：
11.2
作者：
ALEXIANU, ME;HO, BK;APPEL, SH
通讯作者：
APPEL, SH
影响因子：
2.5
作者：
HUGON, J;VALLAT, JM;BARTHE, D
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BARTHE, D
影响因子：
5.5
作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
3.4
作者：
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通讯作者：
Rosenberg, PA