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Gene Review

Npc1  -  Niemann-Pick type C1

Mus musculus

Synonyms: A430089E03Rik, C85354, D18Ertd139e, D18Ertd723e, Niemann-Pick C1 protein, ...
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Disease relevance of Npc1

  • By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs [1].
  • Niemann-Pick type C (NPC) is a neurodegenerative disorder with somatically altered cholesterol metabolism [2].
  • Both human and murine NPC are characterized neuropathologically by ballooned neurons distended with lipid storage, axonal spheroid formation, demyelination, and widespread neuronal loss [3].
  • The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7 [4].
  • We found significant but relatively small improvements in rate of disease progression by treating Npc1-/- mice with tamoxifen and/or vitamin E. Some sex differences in response and an early improvement in Rota-Rod performance suggest areas for further study [5].

Psychiatry related information on Npc1


High impact information on Npc1


Chemical compound and disease context of Npc1


Biological context of Npc1

  • Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene [10].
  • Nuclear concentrations and DNA binding activity of NF-kappaB's transactivation subunit, p65, were significantly reduced in Npc1-/- mice compared to Npc1+/+ mice [6].
  • In adult animals of both genotypes, the Npc1 mRNA was detected in the majority of neurons in nearly all regions, but at significantly higher levels in the cerebellum and in specific pontine nuclei [11].
  • Niemann-Pick type C (NPC) disease is caused by mutations to genes that encode proteins critical to intracellular lipid homeostasis [6].
  • To define further the relationship between caveolin-1 function and the cholesterol trafficking defect in NPC, we examined the expression and distribution of additional caveolar and signal transduction proteins [12].

Anatomical context of Npc1


Associations of Npc1 with chemical compounds

  • Furthermore, net loss of cholesterol from the CNS is much higher in the NPC mouse than in the control animal (2.23 versus 1.37 mg/day per kg) so that the concentration of sterol in most regions of the brain is reduced [15].
  • We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity [4].
  • Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice [4].
  • GSL and cholesterol levels were increased in mutant NPC1-null Chinese hamster ovary cells as well as U18666A and progesterone induced NPC cell culture models [18].
  • Altered BODIPY lactosylceramide targeting, decreased endocytic uptake of a fluid phase marker, and mistargeting of annexin 2 (phenotypes associated with NPC) are reversed by inhibition of GSL synthesis [18].
  • We focused on the role of the AP-3 pathway in the targeting of the mammalian NP-C proteins [19].
  • These results provide strong evidence that cholesterol accumulation-induced changes in autophagy-lysosome function are closely associated with neurodegeneration in NPC [20].

Physical interactions of Npc1


Regulatory relationships of Npc1

  • Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice [21].

Other interactions of Npc1

  • Perturbations of nuclear factor (NF)-kappaB, which is regulated by GSK-3beta, occurred in Npc1-/- mouse brains [6].
  • Here, we analyze the effects of genetically depriving NPC neurons of complex gangliosides by creating mice doubly deficient in both NPC1 and the GSL synthetic enzyme, GM2/GD2 synthase (GalNAcT) [22].
  • Using the BALB/c murine model for NPC disease, we found that the expression of caveolin-1 in total liver homogenates from heterozygous and homozygous affected animals was altered [23].
  • Our data suggest that focal deregulation of cdk5/p25 in axons leads to cytoskeletal abnormalities and eventual neurodegeneration in NPC [3].
  • Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet [21].

Analytical, diagnostic and therapeutic context of Npc1

  • We have used in situ hybridization techniques to characterize the pattern of Npc1 mRNA expression in both the wild-type and the npc(nih) mutant mouse brain [11].
  • In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis [21].
  • Based on a highly homologous domain, we designed primers to look for levels of Npc1 mRNA with a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) approach using cyclophilin as an internal standard [14].
  • The decreased sperm number in Npc1(-/-) mice is due, at least in part, to partial arrest of spermatogenesis in the testes, as revealed by histological analysis [24].
  • The sciatic nerve of the mouse mutant with Niemann-Pick type C disease (NPC mouse) was investigated using light and electron microscopy, and teased-fiber preparations [25].


  1. Cholesterol accumulation in tissues of the Niemann-pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ. Xie, C., Turley, S.D., Dietschy, J.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann-Pick C mice. Erickson, R.P., Garver, W.S., Camargo, F., Hossain, G.S., Heidenreich, R.A. J. Inherit. Metab. Dis. (2000) [Pubmed]
  3. Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. Bu, B., Li, J., Davies, P., Vincent, I. J. Neurosci. (2002) [Pubmed]
  4. Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. Ahmad, I., Lope-Piedrafita, S., Bi, X., Hicks, C., Yao, Y., Yu, C., Chaitkin, E., Howison, C.M., Weberg, L., Trouard, T.P., Erickson, R.P. J. Neurosci. Res. (2005) [Pubmed]
  5. Tamoxifen and vitamin E treatments delay symptoms in the mouse model of Niemann-Pick C. Bascuñan-Castillo, E.C., Erickson, R.P., Howison, C.M., Hunter, R.J., Heidenreich, R.H., Hicks, C., Trouard, T.P., Gillies, R.J. J. Appl. Genet. (2004) [Pubmed]
  6. Deregulation of the phosphatidylinositol-3 kinase signaling cascade is associated with neurodegeneration in Npc1-/- mouse brain. Bi, X., Liu, J., Yao, Y., Baudry, M., Lynch, G. Am. J. Pathol. (2005) [Pubmed]
  7. Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Griffin, L.D., Gong, W., Verot, L., Mellon, S.H. Nat. Med. (2004) [Pubmed]
  8. Niemann pick type C disease as a model for defects in neurosteroidogenesis. Mellon, S., Gong, W., Griffin, L.D. Endocr. Res. (2004) [Pubmed]
  9. Tissue culture methods to study neurological disorders: establishment of immortalized Schwann cells from murine disease models. Watabe, K., Sakamoto, T., Kawazoe, Y., Michikawa, M., Miyamoto, K., Yamamura, T., Saya, H., Araki, N. Neuropathology : official journal of the Japanese Society of Neuropathology. (2003) [Pubmed]
  10. Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. Loftus, S.K., Erickson, R.P., Walkley, S.U., Bryant, M.A., Incao, A., Heidenreich, R.A., Pavan, W.J. Hum. Mol. Genet. (2002) [Pubmed]
  11. Regional and developmental expression of the Npc1 mRNA in the mouse brain. Prasad, A., Fischer, W.A., Maue, R.A., Henderson, L.P. J. Neurochem. (2000) [Pubmed]
  12. The Npc1 mutation causes an altered expression of caveolin-1, annexin II and protein kinases and phosphorylation of caveolin-1 and annexin II in murine livers. Garver, W.S., Hossain, G.S., Winscott, M.M., Heidenreich, R.A. Biochim. Biophys. Acta (1999) [Pubmed]
  13. The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals. Karten, B., Campenot, R.B., Vance, D.E., Vance, J.E. J. Lipid Res. (2006) [Pubmed]
  14. Expression of Niemann-Pick type C transcript in rodent cerebellum in vivo and in vitro. Falk, T., Garver, W.S., Erickson, R.P., Wilson, J.M., Yool, A.J. Brain Res. (1999) [Pubmed]
  15. Cholesterol is sequestered in the brains of mice with Niemann-Pick type C disease but turnover is increased. Xie, C., Burns, D.K., Turley, S.D., Dietschy, J.M. J. Neuropathol. Exp. Neurol. (2000) [Pubmed]
  16. Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo. Burns, M., Gaynor, K., Olm, V., Mercken, M., LaFrancois, J., Wang, L., Mathews, P.M., Noble, W., Matsuoka, Y., Duff, K. J. Neurosci. (2003) [Pubmed]
  17. Lipid homeostasis and lipoprotein secretion in Niemann-Pick C1-deficient hepatocytes. Kulinski, A., Vance, J.E. J. Biol. Chem. (2007) [Pubmed]
  18. Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. te Vruchte, D., Lloyd-Evans, E., Veldman, R.J., Neville, D.C., Dwek, R.A., Platt, F.M., van Blitterswijk, W.J., Sillence, D.J. J. Biol. Chem. (2004) [Pubmed]
  19. The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3. Berger, A.C., Salazar, G., Styers, M.L., Newell-Litwa, K.A., Werner, E., Maue, R.A., Corbett, A.H., Faundez, V. J. Cell. Sci. (2007) [Pubmed]
  20. Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1 -/- mouse brain. Liao, G., Yao, Y., Liu, J., Yu, Z., Cheung, S., Xie, A., Liang, X., Bi, X. Am. J. Pathol. (2007) [Pubmed]
  21. Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet. Erickson, R.P., Bhattacharyya, A., Hunter, R.J., Heidenreich, R.A., Cherrington, N.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  22. Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Gondré-Lewis, M.C., McGlynn, R., Walkley, S.U. Curr. Biol. (2003) [Pubmed]
  23. Altered expression of caveolin-1 and increased cholesterol in detergent insoluble membrane fractions from liver in mice with Niemann-Pick disease type C. Garver, W.S., Erickson, R.P., Wilson, J.M., Colton, T.L., Hossain, G.S., Kozloski, M.A., Heidenreich, R.A. Biochim. Biophys. Acta (1997) [Pubmed]
  24. Sperm defects in mice lacking a functional Niemann-Pick C1 protein. Fan, J., Akabane, H., Graham, S.N., Richardson, L.L., Zhu, G.Z. Mol. Reprod. Dev. (2006) [Pubmed]
  25. Peripheral nerve pathology in Niemann-Pick type C mouse. Higashi, Y., Murayama, S., Pentchev, P.G., Suzuki, K. Acta Neuropathol. (1995) [Pubmed]
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