Novel role of a Ca^<2+>-binding protein NCS-1 as a survival promoting factor

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。在这里，我们证明了神经元Ca^2+传感器1（NCS-1），各种神经元功能的关键蛋白之一，也作为一个重要的神经元存活因子。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）处理后表达增加，并以Akt依赖但MAPK不依赖的方式介导GDNF存活信号。此外，NCS-1在成年大鼠DMV神经元中响应于轴突切断诱导的损伤而显著上调，并且E120 Q的腺病毒过表达导致存活神经元的显著损失，表明NCS-1参与成年运动神经元中的抗凋亡机制。综上所述，我们认为NCS-1是一种新的在损伤神经元中上调的生存促进因子，通过Akt途径介导GDNF-生存信号。

Molecular basis of survival from neuronal injury is essential for development of therapeutic strategy to remedy neurodegenerative disorders. Here, we demonstrate that neuronal Ca^<2+>-sensor 1 (NCS-1) ; one of key proteins for various neuronal functions also acts as an important neuronal survival factor. Overexpression of NCS-1 rendered cultured neurons more tolerant to cell death caused by several kinds of stressors ; while 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 a Akt-dependent but MAPK-independent manner. Furthermore, NCS-1 is significantly up-regulated in response to axotomy-induced injury in the DMV 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 anti-apoptotic mechanism in adult motor neurons. Taken together, we propose that NCS-1 is a novel survival-promoting factor up-regulated in injured neurons, mediating the GDNF-survival signal via Akt pathway.