The role of presenilin cofactors in the γ-secretase complex

Nobumasa Takasugi, Taisuke Tomita (), Ikuo Hayashi, Makiko Tsuruoka, Manabu Niimura, Yasuko Takahashi, Gopal Thinakaran and Takeshi Iwatsubo ()
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Nobumasa Takasugi: University of Tokyo
Taisuke Tomita: University of Tokyo
Ikuo Hayashi: University of Tokyo
Makiko Tsuruoka: University of Tokyo
Manabu Niimura: University of Tokyo
Yasuko Takahashi: University of Tokyo
Gopal Thinakaran: The University of Chicago
Takeshi Iwatsubo: University of Tokyo

Nature, 2003, vol. 422, issue 6930, 438-441

Abstract: 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)1,2. Cleavage of βAPP by FAD mutant presenilin results in the overproduction of highly amyloidogenic amyloid β42 peptides3,4,5,6. γ-Secretase activity requires the formation of a stable, high-molecular-mass protein complex7,8,9,10,11 that, in addition to the endoproteolysed fragmented form of presenilin, contains essential cofactors including nicastrin12,13,14, 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.

Date: 2003
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DOI: 10.1038/nature01506

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