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Gene Review

Ncstn  -  nicastrin

Mus musculus

Synonyms: 9430068N19Rik, AA727311, Aph2, D1Dau13e, Kiaa0253, ...
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Psychiatry related information on Ncstn


High impact information on Ncstn

  • Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function [2].
  • Gamma-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex [3].
  • Interestingly, significant amounts of full-length PS1 and PEN-2, but not APH-1, are detected on the plasma membrane in Nct KO cells, suggesting the Nct-independent cell surface delivery of the PEN-2.PS1 [4].
  • Presenilin 1 and presenilin 2 have differential effects on the stability and maturation of nicastrin in Mammalian brain [5].
  • Post-translational glycosylation and trafficking of nicastrin is necessary for the activity of these complexes [5].

Biological context of Ncstn


Anatomical context of Ncstn

  • In adult mouse, nicastrin is highly expressed in muscle membranes, whereas presenilin levels are very low [9].
  • We also show that endogenous PEN2 expression was drastically higher in wild-type than in PS- and Nct-deficient fibroblasts and was enhanced by proteasome inhibitors only in the two deficient cell systems [10].
  • Nicastrin-null embryos died by embryonic day 10.5 and exhibited several patterning defects, including abnormal somite segmentation, phenotypes that are reminiscent of embryos lacking Notch1 or both presenilins [11].
  • In N2a and 293 cell lines that stably overexpress PS1, APH-1, NCT, and PEN-2, PS1 fragment levels are elevated by up to 10-fold over endogenous levels [12].
  • AVs were also the most enriched subcellular fraction in levels of the gamma-secretase components presenilin and nicastrin [13].

Associations of Ncstn with chemical compounds

  • After RA treatment the NICA siRNA clone failed to differentiate completely into networks of neurons [14].

Physical interactions of Ncstn

  • Together, these results establish that nicastrin is an essential component of the multimeric gamma-secretase complex in mammals required for both gamma-secretase activity and APP trafficking and suggest that nicastrin may be a valuable therapeutic target for Alzheimer's disease [11].

Other interactions of Ncstn


  1. Loss of nicastrin elicits an apoptotic phenotype in mouse embryos. Nguyen, V., Hawkins, C., Bergeron, C., Supala, A., Huang, J., Westaway, D., St George-Hyslop, P., Rozmahel, R. Brain Res. (2006) [Pubmed]
  2. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Phiel, C.J., Wilson, C.A., Lee, V.M., Klein, P.S. Nature (2003) [Pubmed]
  3. Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Mastrangelo, P., Mathews, P.M., Chishti, M.A., Schmidt, S.D., Gu, Y., Yang, J., Mazzella, M.J., Coomaraswamy, J., Horne, P., Strome, B., Pelly, H., Levesque, G., Ebeling, C., Jiang, Y., Nixon, R.A., Rozmahel, R., Fraser, P.E., St George-Hyslop, P., Carlson, G.A., Westaway, D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components. Zhang, Y.W., Luo, W.J., Wang, H., Lin, P., Vetrivel, K.S., Liao, F., Li, F., Wong, P.C., Farquhar, M.G., Thinakaran, G., Xu, H. J. Biol. Chem. (2005) [Pubmed]
  5. Presenilin 1 and presenilin 2 have differential effects on the stability and maturation of nicastrin in Mammalian brain. Chen, F., Tandon, A., Sanjo, N., Gu, Y.J., Hasegawa, H., Arawaka, S., Lee, F.J., Ruan, X., Mastrangelo, P., Erdebil, S., Wang, L., Westaway, D., Mount, H.T., Yankner, B., Fraser, P.E., St George-Hyslop, P. J. Biol. Chem. (2003) [Pubmed]
  6. Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype. Rozmahel, R., Mount, H.T., Chen, F., Nguyen, V., Huang, J., Erdebil, S., Liauw, J., Yu, G., Hasegawa, H., Gu, Y., Song, Y.Q., Schmidt, S.D., Nixon, R.A., Mathews, P.M., Bergeron, C., Fraser, P., Westaway, D., St George-Hyslop, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Neprilysin activity and expression are controlled by nicastrin. Pardossi-Piquard, R., Dunys, J., Yu, G., St George-Hyslop, P., Alves da Costa, C., Checler, F. J. Neurochem. (2006) [Pubmed]
  8. APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. Ma, G., Li, T., Price, D.L., Wong, P.C. J. Neurosci. (2005) [Pubmed]
  9. Nicastrin expression in mouse peripheral tissues is not co-ordinated with presenilin and is high in muscle. Ilaya, N.T., Evin, G., Masters, C.L., Culvenor, J.G. J. Neurochem. (2004) [Pubmed]
  10. Catabolism of endogenous and overexpressed APH1a and PEN2: evidence for artifactual involvement of the proteasome in the degradation of overexpressed proteins. Dunys, J., Kawarai, T., Wilk, S., St George-Hyslop, P., Alves da Costa, C., Checler, F. Biochem. J. (2006) [Pubmed]
  11. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. Li, T., Ma, G., Cai, H., Price, D.L., Wong, P.C. J. Neurosci. (2003) [Pubmed]
  12. Regulated hyperaccumulation of presenilin-1 and the "gamma-secretase" complex. Evidence for differential intramembranous processing of transmembrane subatrates. Kim, S.H., Ikeuchi, T., Yu, C., Sisodia, S.S. J. Biol. Chem. (2003) [Pubmed]
  13. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Yu, W.H., Kumar, A., Peterhoff, C., Shapiro Kulnane, L., Uchiyama, Y., Lamb, B.T., Cuervo, A.M., Nixon, R.A. Int. J. Biochem. Cell Biol. (2004) [Pubmed]
  14. Regulatory roles of presenilin-1 and nicastrin in neuronal differentiation during in vitro neurogenesis. Sarkar, S.N., Das, H.K. J. Neurochem. (2003) [Pubmed]
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