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J. Biol. Chem., Vol. 277, Issue 51, 50198-50205, December 20, 2002

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The Mechanism of -Secretase Activities through High Molecular Weight Complex Formation of Presenilins Is Conserved in Drosophila melanogaster and Mammals^*

Nobumasa Takasugi, Yasuko Takahashi, Yuichi Morohashi, Taisuke Tomita, and Takeshi Iwatsubo

From the Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-0033

Mutations in presenilin 1 (PS1) and PS2 genes contribute to the pathogenesis of early onset familial Alzheimer's disease by increasing secretion of the pathologically relevant A42 polypeptides. PS genes are also implicated in Notch signaling through proteolytic processing of the Notch receptor in Caenorhabditis elegans, Drosophila melanogaster, and mammals. Here we show that Drosophila PS (Psn) protein undergoes endoproteolytic cleavage and forms a stable high molecular weight (HMW) complex in Drosophila S2 or mouse neuro2a (N2a) cells in a similar manner to mammalian PS. The loss-of-function recessive point mutations located in the C-terminal region of Psn, that cause an early pupal-lethal phenotype resembling Notch mutant in vivo, disrupted the HMW complex formation, and abolished -secretase activities in cultured cells. The overexpression of Psn in mouse embryonic fibroblasts lacking PS1 and PS2 genes rescued the Notch processing. Moreover, disruption of the expression of Psn by double-stranded RNA-mediated interference completely abolished the -secretase activity in S2 cells. Surprisingly, -secretase activity dependent on wild-type Psn was associated with a drastic overproduction of A1-42 from human APP in N2a cells, but not in S2 cells. Our data suggest that the mechanism of -secretase activities through formation of HMW PS complex, as well as its abolition by loss-of-function mutations located in the C terminus, are highly conserved features in Drosophila and mammals.

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