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Gene Review

NCSTN  -  nicastrin

Homo sapiens

Synonyms: APH2, KIAA0253, Nicastrin, UNQ1874/PRO4317
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Disease relevance of NCSTN

  • The addition to APP-C99-infected cells of baculoviruses bearing nicastrin, also a transmembrane protein, had a neutral or inhibitory effect on the reaction; tropomyosin viruses had the same effect as nicastrin viruses [1].
  • These observations suggested that nicastrin, as well as the APP and PS proteins, were also involved in the upregulated Bax mediated neuroblastoma cell death and the release of cytochrome c in the neuroblastoma [2].

Psychiatry related information on NCSTN

  • Furthermore, we found an intronic +17G>C polymorphism in PEN2 which, in homozygous form, was greater in early onset Alzheimer's disease (EOAD) compared to controls, and one haplotype in the NCSTN gene which was linked to EOAD and familial AD (FAD) [3].

High impact information on NCSTN


Biological context of NCSTN

  • In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y) [9].
  • Very similar to a loss of PS function, down-regulation of Nct levels leads to a massive accumulation of the C-terminal fragments of the beta-amyloid precursor protein [10].
  • Furthermore, we have down-regulated Nct levels by using a highly specific and efficient RNA interference approach [10].
  • To avoid the misfolding phenotype often associated with introducing deletions or mutations into heavily glycosylated and disulfide-bonded proteins such as NCT, we produced chimeras between human (hNCT) and Caenorhabditis elegans NCT (ceNCT) [11].
  • Interestingly, cells derived from Nicastrin heterozygotes produced relatively higher levels of amyloid beta-peptide whether the source was endogenous mouse or transfected human APP [12].

Anatomical context of NCSTN


Associations of NCSTN with chemical compounds

  • To investigate the function of this glycoprotein, we compared nicastrin and presenilin protein expression in various mouse tissues [14].
  • The levels of nicastrin mRNA, however, were unaltered in SK-N-SH, IMR-32, U-373MG, and NTera2-N cells by exposure to the factors tested, and unchanged in NTera2 cells during retinoic acid-induced neuronal differentiation [18].
  • Here we report the identification of Abl-philin 2 (Aph2), encoding a novel protein with a unique cysteine-rich motif (zf-DHHC) and a 53-amino acid stretch sharing homology with the creatine kinase family [19].
  • Addition of 5 M urea caused complex dissolution and nicastrin to migrate as a subcomplex [20].

Physical interactions of NCSTN


Enzymatic interactions of NCSTN

  • Our results show that ERK1/2 is an endogenous regulator of gamma-secretase, which raises the possibility that ERK1/2 down-regulates gamma-secretase activity by directly phosphorylating nicastrin [22].

Regulatory relationships of NCSTN

  • Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation [10].
  • We investigated the effects of differing levels of the immature and mature endoglycosidase-H-resistant forms of nicastrin on Abeta40- and Abeta42-peptide secretion in several cell lines stably expressing a mutant nicastrin (D336A/Y337A) that increases Abeta secretion [23].

Other interactions of NCSTN

  • The result suggests no apparent synergic interaction between the NCSTN and APOE epsilon 4 in the risk to develop the late onset sporadic form of AD [24].
  • We conclude that cooperative effects may stabilize a trim-eric complex of APH-1a G122D together with PS1 and NCT [25].
  • Differences in the levels of mature mutant nicastrin positively correlated with Abeta secretion, but did not influence either betaAPP trafficking or processing by alpha- and beta-secretases [23].
  • Interestingly, overexpression of ubiquilin resulted in a decrease in Pen-2 and nicastrin levels, two essential components of the gamma-secretase complex [26].
  • Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities [7].

Analytical, diagnostic and therapeutic context of NCSTN

  • Under normal cell culture conditions, only mature nicastrin is expressed at the cell surface and binds to the presenilin heterodimers [27].
  • Sensitive techniques of multiple sequence alignment extend the earlier observation of the aminopeptidase homology domain in nicastrin to suggest that this protein may be a catalytically active component of secretasome involved in proteolysis or co-proteolysis of presenilin or beta-amyloid [28].
  • Overexpression of Aph2 leads to apoptosis as justified by TUNEL assays, and the induction of apoptosis requires the N terminus [19].
  • Deletion analysis by two-hybrid assays revealed that the N-terminal portion of Aph2 interacts with the C terminus of c-Abl [19].
  • Molecular cloning and characterization of human Aph2 gene, involved in AP-1 regulation by interaction with JAB1 [29].


  1. Baculoviruses expressing the human familial Alzheimer's disease presenilin 1 mutation lacking exon 9 increase levels of an amyloid beta-like protein in Sf9 cells. Verdile, G., Groth, D., Mathews, P.M., St George-Hyslop, P., Fraser, P.E., Ramabhadran, T.V., Kwok, J.B., Schofield, P.R., Carter, T., Gandy, S., Martins, R.N. Mol. Psychiatry (2004) [Pubmed]
  2. Mutant nicastrin protein can induce the cytochrome c release and the Bax expression. Hwang, D.Y., Kim, Y.K., Lim, C.J., Cho, J.S. Int. J. Neurosci. (2004) [Pubmed]
  3. Genetic study of Sardinian patients with Alzheimer's disease. Piscopo, P., Manfredi, A., Malvezzi-Campeggi, L., Crestini, A., Spadoni, O., Cherchi, R., Deiana, E., Piras, M.R., Confaloni, A. Neurosci. Lett. (2006) [Pubmed]
  4. Nicastrin functions as a gamma-secretase-substrate receptor. Shah, S., Lee, S.F., Tabuchi, K., Hao, Y.H., Yu, C., LaPlant, Q., Ball, H., Dann, C.E., Südhof, T., Yu, G. Cell (2005) [Pubmed]
  5. Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Haass, C., Steiner, H. Trends Cell Biol. (2002) [Pubmed]
  6. Reconstitution of gamma-secretase activity. Edbauer, D., Winkler, E., Regula, J.T., Pesold, B., Steiner, H., Haass, C. Nat. Cell Biol. (2003) [Pubmed]
  7. Nicastrin binds to membrane-tethered Notch. Chen, F., Yu, G., Arawaka, S., Nishimura, M., Kawarai, T., Yu, H., Tandon, A., Supala, A., Song, Y.Q., Rogaeva, E., Milman, P., Sato, C., Yu, C., Janus, C., Lee, J., Song, L., Zhang, L., Fraser, P.E., St George-Hyslop, P.H. Nat. Cell Biol. (2001) [Pubmed]
  8. Nicastrin, a presenilin-interacting protein, contains an aminopeptidase/transferrin receptor superfamily domain. Fagan, R., Swindells, M., Overington, J., Weir, M. Trends Biochem. Sci. (2001) [Pubmed]
  9. The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample. Dermaut, B., Theuns, J., Sleegers, K., Hasegawa, H., Van den Broeck, M., Vennekens, K., Corsmit, E., St George-Hyslop, P., Cruts, M., van Duijn, C.M., Van Broeckhoven, C. Am. J. Hum. Genet. (2002) [Pubmed]
  10. Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Edbauer, D., Winkler, E., Haass, C., Steiner, H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  11. The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex. Morais, V.A., Crystal, A.S., Pijak, D.S., Carlin, D., Costa, J., Lee, V.M., Doms, R.W. J. Biol. Chem. (2003) [Pubmed]
  12. Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model. Li, J., Fici, G.J., Mao, C.A., Myers, R.L., Shuang, R., Donoho, G.P., Pauley, A.M., Himes, C.S., Qin, W., Kola, I., Merchant, K.M., Nye, J.S. J. Biol. Chem. (2003) [Pubmed]
  13. 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]
  14. 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]
  15. Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane. Kaether, C., Lammich, S., Edbauer, D., Ertl, M., Rietdorf, J., Capell, A., Steiner, H., Haass, C. J. Cell Biol. (2002) [Pubmed]
  16. Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. Yang, D.S., Tandon, A., Chen, F., Yu, G., Yu, H., Arawaka, S., Hasegawa, H., Duthie, M., Schmidt, S.D., Ramabhadran, T.V., Nixon, R.A., Mathews, P.M., Gandy, S.E., Mount, H.T., St George-Hyslop, P., Fraser, P.E. J. Biol. Chem. (2002) [Pubmed]
  17. Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. Pasternak, S.H., Bagshaw, R.D., Guiral, M., Zhang, S., Ackerley, C.A., Pak, B.J., Callahan, J.W., Mahuran, D.J. J. Biol. Chem. (2003) [Pubmed]
  18. Nicastrin, a key regulator of presenilin function, is expressed constitutively in human neural cell lines. Satoh, J., Kuroda, Y. Neuropathology : official journal of the Japanese Society of Neuropathology. (2001) [Pubmed]
  19. Aph2, a protein with a zf-DHHC motif, interacts with c-Abl and has pro-apoptotic activity. Li, B., Cong, F., Tan, C.P., Wang, S.X., Goff, S.P. J. Biol. Chem. (2002) [Pubmed]
  20. Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations. Culvenor, J.G., Ilaya, N.T., Ryan, M.T., Canterford, L., Hoke, D.E., Williamson, N.A., McLean, C.A., Masters, C.L., Evin, G. Eur. J. Biochem. (2004) [Pubmed]
  21. BACE1 interacts with nicastrin. Hattori, C., Asai, M., Oma, Y., Kino, Y., Sasagawa, N., Saido, T.C., Maruyama, K., Ishiura, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  22. ERK1/2 is an endogenous negative regulator of the gamma-secretase activity. Kim, S.K., Park, H.J., Hong, H.S., Baik, E.J., Jung, M.W., Mook-Jung, I. FASEB J. (2006) [Pubmed]
  23. The levels of mature glycosylated nicastrin are regulated and correlate with gamma-secretase processing of amyloid beta-precursor protein. Arawaka, S., Hasegawa, H., Tandon, A., Janus, C., Chen, F., Yu, G., Kikuchi, K., Koyama, S., Kato, T., Fraser, P.E., St George-Hyslop, P. J. Neurochem. (2002) [Pubmed]
  24. Association analysis between Alzheimer's disease and the Nicastrin gene polymorphisms. Orlacchio, A., Kawarai, T., Polidoro, M., Stefani, A., Orlacchio, A., St George-Hyslop, P.H., Bernardi, G. Neurosci. Lett. (2002) [Pubmed]
  25. Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1. Edbauer, D., Kaether, C., Steiner, H., Haass, C. J. Biol. Chem. (2004) [Pubmed]
  26. Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Massey, L.K., Mah, A.L., Monteiro, M.J. Biochem. J. (2005) [Pubmed]
  27. gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. Herreman, A., Van Gassen, G., Bentahir, M., Nyabi, O., Craessaerts, K., Mueller, U., Annaert, W., De Strooper, B. J. Cell. Sci. (2003) [Pubmed]
  28. Refining structural and functional predictions for secretasome components by comparative sequence analysis. Mushegian, A. Proteins (2002) [Pubmed]
  29. Molecular cloning and characterization of human Aph2 gene, involved in AP-1 regulation by interaction with JAB1. Zhang, F., Di, Y., Li, J., Shi, Y., Zhang, L., Wang, C., He, X., Liu, Y., Wan, D., Huo, K., Gu, J. Biochim. Biophys. Acta (2006) [Pubmed]
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