Impaired functions of neural stem cells by abnormal nitric oxide-mediated signaling in an in vitro model of Niemann-Pick type C disease

Nitric oxide （NO） has been implicated in the promotion of neurodegeneration. However, little is known about the relationship between NO and the self-renewal or differentiation capacity of neural stem cells （NSCs） in neurodegenerative disease. In this study, we investigated the effect of NO on self-renewal of NSCs in an animal model for Niemann-Pick type C （NPC） disease. We found that NO production was significantly increased in NSCs from NPCl-deficient mice （NPCI^-/-）, which showed reduced NSC self-renewal. The number of nestin-positive cells and the size of neurospheres were both significantly decreased. The expression of NO synthase （NOS） was increased in neurospheres derived from the brain of NPC1^-/- mice in comparison to wild-type neurospheres. NO-mediated activation of glycogen synthase ki- nase-3β （GSK3β） and caspase-3 was also observed in NSCs from NPC1^-/- mice. The self-renewal ability of NSCs from NPC1^-/- mice was restored by an NOS inhibitor, L-NAME, which resulted in the inhibition of GSK3β and caspase-3. In addition, the differentiation ability of NSCs was partially restored and the number of Fluoro-Jade C-positive degenerating neurons was reduced. These data suggest that overproduction of NO in NPC disease impaired the self-renewal of NSCs. Control of NO production may be key for the treatment of NPC disease.