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

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Kim, Sun-Jung; Lim, Myung-Sin; Kang, Soo Kyung; Lee, Yong Soon; Kang, Kyung-Sun
Issue Date
Nature Publishing Group
Cell Res 2008; 18:686-694
neural stem cellsnitric oxideGSK3βNiemann-Pick type C1 diseasecaspase-3
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 NPC1-deficient mice (NPC1- /- ), 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 kinase-3 (GSK3) 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 GSK3 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.
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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