Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons
Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons
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DOI：
10.1083/jcb.200508156
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发表时间：
2006-03-27
影响因子：
7.8
通讯作者：
Nabekura, J
中科院分区：
文献类型：
--
作者：
Nakamura, TY;Jeromin, A;Nabekura, J
神经元损伤后存活的分子基础对于开发治疗神经退行性疾病的治疗策略至关重要。在这项研究中，我们证明了EF-手钙结合蛋白神经元钙传感器-1（NCS-1），各种神经元功能的关键蛋白之一，也作为一个重要的生存因子。NCS-1的过表达使培养的神经元对多种应激引起的细胞死亡具有更强的耐受性，而显性失活突变体（E120 Q）则加速了这种耐受性。此外，NCS-1蛋白在胶质细胞源性神经营养因子（GDNF）处理后增加，并以Akt（而非MAPK）依赖的方式介导GDNF存活信号。此外，NCS-1是显着上调响应轴突切断诱导损伤的成年大鼠迷走神经元的背侧运动核在体内，和腺病毒过表达E120 Q导致存活的神经元的显着损失，表明NCS-1是参与成年运动神经元的抗凋亡机制。我们认为NCS-1是一种新的存活促进因子，在损伤的神经元中上调，通过磷脂酰肌醇3-激酶-Akt通路介导GDNF存活信号。
A molecular basis of survival from neuronal injury is essential for the development of therapeutic strategy to remedy neurodegenerative disorders. In this study, we demonstrate that an EF-hand Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1), one of the key proteins for various neuronal functions, also acts as an important survival factor. Overexpression of NCS-1 rendered cultured neurons more tolerant to cell death caused by several kinds of stressors, whereas the dominant-negative mutant (E120Q) accelerated it. In addition, NCS-1 proteins increased upon treatment with glial cell line-derived neurotrophic factor ( GDNF) and mediated GDNF survival signal in an Akt (but not MAPK)-dependent manner. Furthermore, NCS-1 is significantly up-regulated in response to axotomy-induced injury in the dorsal motor nucleus of the vagus neurons of adult rats in vivo, and adenoviral overexpression of E120Q resulted in a significant loss of surviving neurons, suggesting that NCS-1 is involved in an antiapoptotic mechanism in adult motor neurons. We propose that NCS-1 is a novel survival-promoting factor up-regulated in injured neurons that mediates the GDNF survival signal via the phosphatidylinositol 3-kinase-Akt pathway.