Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity
Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity
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DOI：
10.1111/j.1471-4159.2012.07746.x
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发表时间：
2012-07-01
影响因子：
4.7
通讯作者：
Takahashi, Hitoshi
中科院分区：
文献类型：
--
作者：
Fujiwara, Takeshi;Morimoto, Koji;Takahashi, Hitoshi
J·神经化学。(2012年)122,162174。摘要谷氨酸兴奋性毒性可导致神经元功能障碍和变性。它与慢性疾病有关，包括阿尔茨海默病，以及急性中枢神经系统损伤，如缺血。这些疾病具有显著的形态特征，包括轴突变性和细胞体死亡。然而，兴奋性毒性诱导神经变性的分子机制仍然知之甚少。神经退行性变的一个关键的分子特征是基于微管的货物运输的缺陷，该运输在维持轴突的生存和应激信号的平衡方面起着关键作用。我们在原代神经元培养中开发了一种兴奋性毒性诱导的神经变性系统。我们发现，兴奋性毒性产生一种C端截短形式的p150Glued，这是动力蛋白复合体的主要成分，它加剧了轴突的退化。在阿尔茨海默病患者的脑组织中发现了这种p150Glut截短形式。野生型(WT)动力蛋白中间链(DIC)是一种与p150Glued相互作用并连接动力蛋白和动力蛋白复合体的动力蛋白成分，DIC(S84D)突变体和WT p150Glued抑制轴突变性。P150Glued和DIC对兴奋性毒性诱导的轴突变性的这些调控作用也在细胞凋亡和细胞体死亡中观察到。因此，我们的发现确定逆行转运蛋白p150Glued和DIC是谷氨酸兴奋毒性诱导的神经退行性变的新的调节剂。
J. Neurochem. (2012) 122, 162174. Abstract Glutamate excitotoxicity causes neuronal dysfunction and degeneration. It is implicated in chronic disorders, including Alzheimers disease, and in acute CNS insults such as ischemia. These disorders share prominent morphological features, including axon degeneration and cell body death. However, the molecular mechanism underlying excitotoxicity-induced neurodegeneration remains poorly understood. A key molecular feature of neurodegeneration is deficits in microtubule-based cargo transport that plays a pivotal role in maintaining the balance of survival and stress signaling in the axon. We developed an excitotoxicity-induced neurodegeneration system in primary neuronal cultures. We find that excitotoxicity generates a C-terminal truncated form of p150Glued, a major component of the dynactin complex, which exacerbates axon degeneration. This p150Glued truncated form was identified in brain tissues of patients with Alzheimers disease. Overexpression of wild-type (WT) dynein intermediate chain (DIC), a dynein component that interacts with p150Glued and links dynein and dynactin complexes, DIC (S84D) mutant, and WT p150Glued suppressed axon degeneration. These modulating effects of p150Glued and DIC on excitotoxicity-induced axon degeneration are also observed in apoptosis and cell body death. Thus, our findings identify retrograde transport proteins, p150Glued and DIC, as novel modulators of neurodegeneration induced by glutamate excitotoxicity.