Abstract
The presenilins and nicastrin form high molecular mass, multimeric protein complexes involved in the intramembranous proteolysis of several proteins. Post-translational glycosylation and trafficking of nicastrin is necessary for the activity of these complexes. We report here that although there are differences in the post-translational processing of nicastrin in neurons and glia, both of the presenilins are required for the physiological post-translational modification and for the correct subcellular distribution of nicastrin. Absence of presenilin 1 (PS1) is associated with dramatic reductions in the level of mature glycosylated nicastrin and with redistribution of nicastrin away from the cell surface. In contrast, absence of presenilin 2 (PS2) is associated with only modest reductions in the levels of immature nicastrin. It is notable that these differential effects parallel the differential effects of null mutations in PS1 and PS2 on APP and Notch processing. Our data therefore suggest that the differential interactions of PS1 and PS2 with nicastrin reflect different functions for the PS1 and PS2 complexes.
Highlights
The presenilins [1, 2] and nicastrin [3] form high molecular mass complexes that are involved in the intramembranous proteolysis of several proteins, including -amyloid precursor protein (APP)1 and Notch receptor [3,4,5,6,7,8,9]
When the levels of nicastrin expression in PS1Ϫ/Ϫ and wild type mouse brain were compared by normalizing to the level of expression in wild type mice (1.00 Ϯ 0.03), nicastrin was expressed at much lower levels in PS1Ϫ/Ϫ brain (0.52 Ϯ 0.06; p Ͻ 0.001) (Fig. 1)
In contrast to the results reported in fibroblasts [11, 12], there was a reduction in the level of immature nicastrin in brain tissue from PS1Ϫ/Ϫ mice (0.59 Ϯ 0.07) compared with brain tissue from wild type littermates (1.00 Ϯ 0.08; p Ͻ 0.001)
Summary
The PS1Ϫ/Ϫ [13, 14] and PS2Ϫ/Ϫ mice [19] as well as the transgenic lines overexpressing human wild type PS1 (PS1 wild type number 1098) or mutant PS1 (PS1 L286V number 1274 and PS1 M146L number 1) have been described previously [25]. The PS1Ϫ/Ϫ mice have been bred onto a C57BL/6 background that permits enhanced post-natal viability because of a modifier locus on chromosome 1 [13, 14]. The PS1 overexpressing transgenic lines were crossed with PS2Ϫ/Ϫ or PS1Ϫ/Ϫ mice to generate mice overexpressing exogenous PS1 on a PS1Ϫ/Ϫ or PS2Ϫ/Ϫ background. The mice were sacrificed at 6 days or at 3 months of age. The brains were removed, frozen on dry ice, and stored at Ϫ80 °C
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