Just when it was looking as though presenilins were, in all likelihood, responsible for γ-secretase activity, new work by Cupers et al. cautions against making such conclusions. Although cleavage of amyloid precursor protein (APP) is decreased in presenilin 1(PS1)-deficient cells, and completely blocked in PS1- and PS2-doubly deficient cells, the authors looked at the subcellular compartments in which the γ-secretase activity, PS, and APP reside, and because their localizations did not completely coincide ("the spatial paradox"), concluded that PS proteins do not have γ-secretase activity. APP-C99-KK, an APP mutant designed to be an excellent substrate for γ-secretase and retained in the endoplasmic reticulum (ER) where PS1 resides, colocalized with PS1 but was not proteolytically cleaved, indicating that PS1 alone did not have γ-secretase activity. APP-C99-KK-expressing cells treated with brefeldin A, which causes the Golgi complex to disassemble and fuse with the ER, led to the generation of Aβ peptide, a marker of γ-secretase activity, suggesting that some unknown protein or proteins that normally reside downstream in the Golgi complex are required for γ-secretase activity, most likely in the presence of PS1.
P. Cupers, M. Bentahir, K. Craessaerts, I. Orlans, H. Vanderstichele, P. Saftig, B. De Strooper, W. Annaert, The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein. J. Cell Biol. 154, 731-740 (2001). [Abstract] [Full Text]