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.
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.)
