Abstract Aims: We explore the region-specific impact of nitric oxide (NO) on adult neural stem cell (aNSC) niches with regard to neurogenesis and NSC damage and investigate the underlying mechanisms in Niemann-Pick disease type C (NPC) mice. Results: Among the two anatomical stem-cell niches of the brain, subventricular zone (SVZ)-derived aNSCs enhanced c-Jun N-terminal kinase (JNK) activity because of excessive NO production by the cholesterol accumulation. Activated JNK interacts with γH2AX, a marker for DNA damage; however, almost none of the aNSCs in the dentate gyrus (DG) showed either JNK signaling activation or abundant DNA damage. SVZ-derived aNSCs were protected from DNA damage by the treatment of Nω-nitro-L-arginine methyl ester (L-NAME), a NO synthase (NOS) inhibitor, both in vitro and in vivo. We also observed that U18666A, an inducer of cholesterol accumulation, increased inducible NOS expression, JNK activation, and DNA damage in the wild type (WT)-aNSCs. Interestingly, we found that endogenous cholesterol efflux transporters and their regulator were less activated in the SVZ than in the DG, in both WT and NPC mice. This result explains the high vulnerability of SVZ-derived aNSCs to the cholesterol imbalance as observed in NPC mice. Innovation and Conclusion: In this study, we demonstrated that the SVZ-derived aNSCs might be major targets of NPC. Significantly, aNSCs showed different responses depending on their anatomical origins due to dissimilarities in their cholesterol transporting system and NO-dependent JNK activation. These findings can contribute to the understanding of the region-specific nature of the two SVZ and DG neurogenic niches. Antioxid. Redox Signal. 00, 000-000.