PDF(Pubmed)
Abstract：
Excessive levels of glutamate activity could potentially damage and kill neurons. Glutamate excitotoxicity is thought to play a critical role in many CNS and retinal diseases. Accordingly, glutamate excitotoxicity has been used as a model to study neuronal diseases. Immune proteins, such as major histocompatibility complex (MHC) class I molecules and their receptors, play important roles in many neuronal diseases, while T-cell receptors (TCR) are the primary receptors of MHCI. We previously showed that a critical component of TCR, CD3ζ, is expressed by mouse retinal ganglion cells (RGCs). The mutation of CD3ζ or MHCI molecules compromises the development of RGC structure and function. In this study, we investigated whether CD3ζ-mediated molecular signaling regulates RGC death in glutamate excitotoxicity. We show that mutation of CD3ζ significantly increased RGC survival in NMDA-induced excitotoxicity. In addition, we found that several downstream molecules of TCR, including Src (proto-oncogene tyrosine-protein kinase) family kinases (SFKs) and spleen tyrosine kinase (Syk), are expressed by RGCs. Selective inhibition of an SFK member, Hck, or Syk members, Syk or Zap70, significantly increased RGC survival in NMDA-induced excitotoxicity. These results provide direct evidence to reveal the underlying molecular mechanisms that control RGC death under disease conditions.
摘要：
过高的谷氨酸活性水平可能会损害和杀死神经元。谷氨酸兴奋毒性被认为在许多CNS和视网膜疾病中起关键作用。因此，谷氨酸兴奋性毒性已被用作研究神经元疾病的模型。免疫蛋白,如主要组织相容性复合体（MHC）I类分子及其受体，在许多神经元疾病中发挥重要作用，而T细胞受体（TCR）是MHCI的主要受体。我们之前证明了TCR的一个关键组成部分，CD3ζ,由小鼠视网膜神经节细胞(RGC)表达。CD3ζ或MHCI分子的突变损害了RGC结构和功能的发展。在这项研究中,我们研究了CD3ζ介导的分子信号传导是否调节谷氨酸兴奋毒性中的RGC死亡。我们表明，CD3ζ的突变显着增加了NMDA诱导的兴奋性毒性中的RGC存活。此外,我们发现TCR的几个下游分子，包括Src（原癌基因酪氨酸蛋白激酶）家族激酶（SFKs）和脾酪氨酸激酶（Syk），由RGC表示。选择性抑制SFK成员，Hck,或Syk成员，Syk或Zap70在NMDA诱导的兴奋性毒性中显着增加了RGC的存活率。这些结果为揭示疾病条件下控制RGC死亡的潜在分子机制提供了直接证据。
