Cooperative effect of p150Glued and microtubule stabilization to suppress excitotoxicity-induced axon degeneration
Cooperative effect of p150Glued and microtubule stabilization to suppress excitotoxicity-induced axon degeneration
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DOI：
10.1016/j.bbrc.2012.06.071
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发表时间：
2012-07-20
影响因子：
3.1
通讯作者：
Morimoto, Koji
中科院分区：
文献类型：
--
作者：
Fujiwara, Takeshi;Morimoto, Koji
谷氨酸兴奋性毒性与慢性神经系统疾病和急性中枢神经系统损伤有关，并导致包括轴突在内的神经元变性。兴奋性毒性引起的轴突变性的分子机制尚不清楚。最近，我们发现控制微管依赖性逆行运输的动力蛋白-动力蛋白复合物的成分在调节兴奋性毒性诱导的神经变性过程中发挥重要作用。在这里，我们使用海马培养物并寻找与动力蛋白-动力蛋白复合物的成分协同发挥作用的途径，并确定微管稳定作为抑制轴突变性的合作途径。我们发现 p150Glued（dynactin 复合物的主要成分）的过度表达和微管稳定可协同抑制轴突变性。 p150Glued 的保护作用取决于 C 末端区域，因为兴奋毒性诱导的 p150Glued C 末端截短形式无法与 APP 货物相互作用，并在过表达时改变 APP 在神经突中的定位。 p150Glued C 端截短不能通过微管稳定来挽救，这表明 p150Glued 和微管稳定保护轴突变性的下游效应是相互排斥的。 (C) 2012 Elsevier Inc. 保留所有权利。
Glutamate excitotoxicity is implicated in chronic neurological disorders and acute CNS insults and causes neuronal degeneration including axons. The molecular mechanism underlying excitotoxicity-induced axon degeneration is poorly understood. Recently, we found that components of the dynein-dynactin complex that governs microtubule-dependent retrograde transport play important roles in modulating the process of excitotoxicity-induced neurodegeneration. Here we used hippocampal cultures and searched for pathways that function in concert with the components of the dynein-dynactin complex and identified microtubule stabilization as a cooperative pathway to suppress axon degeneration. We find that overexpression of p150Glued, a major component of the dynactin complex, and microtubule stabilization cooperatively suppress axon degeneration. The protective effect of p150Glued is dependent on the C-terminal region as excitotoxicity-induced C-terminal truncated form of p150Glued was unable to interact with APP cargo and altered the localization of APP in neurites when overexpressed. C-terminal truncation of p150Glued is not rescued by microtubule stabilization suggesting that the downstream effects of p150Glued and microtubule stabilization to protect axon degeneration are mutually exclusive. (C) 2012 Elsevier Inc. All rights reserved.