Positive and Negative Regulation of the γ-Secretase Activity by Nicastrin in a Murine Model

Nicastrin is a component of the γ-secretase complex that has been shown to adhere to presenilin-1 (PS1), Notch, and APP. Here we demonstrate that Nicastrin-deficient mice showed a phenotype that is indistinguishable from PS1/PS2 double knock-out mice, whereas heterozygotes were healthy and viable. F...

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Veröffentlicht in:The Journal of biological chemistry 2003-08, Vol.278 (35), p.33445-33449
Hauptverfasser: Li, Jinhe, Fici, Gregory J., Mao, Chai-An, Myers, Richard L., Shuang, Rongqing, Donoho, Gregory P., Pauley, Adele M., Himes, Carol S., Qin, Wenning, Kola, Ismail, Merchant, Kalpana M., Nye, Jeffrey S.
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Sprache:eng
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Zusammenfassung:Nicastrin is a component of the γ-secretase complex that has been shown to adhere to presenilin-1 (PS1), Notch, and APP. Here we demonstrate that Nicastrin-deficient mice showed a phenotype that is indistinguishable from PS1/PS2 double knock-out mice, whereas heterozygotes were healthy and viable. Fibroblasts derived from Nicastrin-deficient embryos were unable to generate amyloid β-peptide and failed to release the intracellular domain of APP- or Notch1-Gal4-VP16 fusion proteins. Additionally, C- and N-terminal fragments of PS1 and the C-terminal fragments of PS2 were not detectable in Nicastrin-null fibroblasts, whereas full-length PS1 accumulated in null fibroblasts, indicating that Nicastrin is required for the endoproteolytic processing of presenilins. Interestingly, cells derived from Nicastrin heterozygotes produced relatively higher levels of amyloid β-peptide whether the source was endogenous mouse or transfected human APP. These data demonstrate that Nicastrin is essential for the γ-secretase cleavage of APP and Notch in mammalian cells and that Nicastrin has both positive and negative functions in the regulation of γ-secretase activity.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M301288200