The role of presenilin cofactors in the γ-secratase complex

Nobumasa Takasugi, Taisuke Tomita, Ikuo Hayashi, Makiko Tsuruoka, Manabu Niimura, Yasuko Takahashi, Gopal Thinakaran, Takeshi Iwatsubo

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Abstract

Mutations in presenilin genes account for the majority of the cases of the familial form of Alzheimer's disease (FAD). Presenilin is essential for γ-secretase activity, a proteolytic activity involved in intramembrane cleavage of Notch and β-amyloid precursor protein (βAPP). Cleavage of βAPP by FAD mutant presenilin results in the overproduction of highly amyloidogenic amyloid β42 peptides. γ-Secretase activity requires the formation of a stable, high-molecular-mass protein complex that, in addition to the endoproteolysed fragmented form of presenilin, contains essential cofactors including nicastrin, APH-1 (refs 15-18) and PEN-2 (refs 16, 19). However, the role of each protein in complex formation and the generation of enzymatic activity is unclear. Here we show that Drosophila APH-1 (Aph-1) increases the stability of Drosophila presenilin (Psn) holoprotein in the complex. Depletion of PEN-2 by RNA interference prevents endoproteolysis of presenilin and promotes stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Co-expression of Drosophila Pen-2 with Aph-1 and nicastrin increases the formation of Psn fragments as well as γ-secretase activity. Thus, APH-1 stabilizes the presenilin holoprotein in the complex, whereas PEN-2 is required for endoproteolytic processing of presenilin and conferring γ-secretase activity to the complex.

Original languageEnglish
Pages (from-to)438-441
Number of pages4
JournalNature
Volume422
Issue number6930
DOIs
Publication statusPublished - Mar 27 2003
Externally publishedYes

ASJC Scopus subject areas

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    Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., & Iwatsubo, T. (2003). The role of presenilin cofactors in the γ-secratase complex. Nature, 422(6930), 438-441. https://doi.org/10.1038/nature01506