Abstract

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 Ca(²⁺)-binding protein neuronal Ca(²⁺) 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.

NEWS SECTION: Journal of Cell Biology, 172:957, 2006.

Neurons survive with NCS-1
A calcium sensor helps save damaged neurons, as reported by Nakamura et al. (page 1081). Calcium is a favorite messenger of neurons . it regulates neurotransmission, signal transduction, and synapse plasticity. The calcium-binding protein NCS-1 translates increased intracellular calcium levels into many of these downstream outcomes. The new results show that NCS-1 also activates antiapoptotic pathways in neurons. Neuronal apoptosis can result from injury or infection. Neurons often survive these insults, however, thanks to activation of the Akt survival pathway by neurotrophic factors such as GDNF. The authors show that this effect requires NCS-1, which is induced by GDNF. When activated by calcium (whose cytoplasmic levels probably increase upon injury), NCS-1 is known to activate phosphoinositide kinases that produce Akt substrates, thus jumpstarting the survival pathway. Loss of NCS-1 hastened cell death in injured rat brains. It also hampered the long-term survival of neurons under normal culture conditions, suggesting that low levels are required even in the absence of injury. As injury strongly increases the levels of NCS-1, its overexpression did not improve survival further. But in diseases in which neuronal survival and regeneration is impaired, boosting NCS-1 activity might have benefical effects.

Published paper

Nakamura TY, Jeromin A, Smith G, Kurushima H, Koga H, Nakabeppu Y, Wakabayashi S & Nabekura J. (2006) Journal of Cell Biology, 172:1081-1091.
(NEWS SECTION: Journal of Cell Biology, 172:957.)