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

• Published in: Cell research Vol. 18; no. 6; pp. 686 - 694
• Main Authors: Kim, Sun-Jung, Lim, Myung-Sin, Kang, Soo-Kyung, Lee, Yong-Soon, Kang, Kyung-Sun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2008; Nature Publishing Group
• Subjects: Animal models; Animals; Biomedical and Life Sciences; Caspase 3 - metabolism; Cell Biology; Cell Death - drug effects; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Disease Models, Animal; Enzyme Activation - drug effects; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Homozygote; Intermediate Filament Proteins - metabolism; Life Sciences; Mice; Nerve Degeneration - pathology; Nerve Tissue Proteins - metabolism; Nestin; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; Neurons - pathology; NG-Nitroarginine Methyl Ester - pharmacology; Niemann-Pick Diseases - metabolism; Niemann-Pick Diseases - pathology; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - metabolism; original-article; Proteins - metabolism; Signal Transduction - drug effects; Stem cells; Stem Cells - drug effects; Stem Cells - enzymology; Stem Cells - metabolism; Stem Cells - pathology; 一氧化氮; 动物模型; 神经干细胞; GSK3β; Niemann-Pick type C1 disease; nitric oxide; neural stem cells; caspase-3
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2008.48

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.