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

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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.