Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations

Abstract

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for approximately 40% of familial AD (FAD) cases. FAD mutations and genetic deletions of presenilins have been associated with calcium (Ca(2+)) signaling abnormalities. We demonstrate that wild-type presenilins, but not PS1-M146V and PS2-N141I FAD mutants, can form low-conductance divalent-cation-permeable ion channels in planar lipid bilayers. In experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs), we find that presenilins account for approximately 80% of passive Ca(2+) leak from the endoplasmic reticulum. Deficient Ca(2+) signaling in DKO MEFs can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants. The ER Ca(2+) leak function of presenilins is independent of their gamma-secretase activity. Our data suggest a Ca(2+) signaling function for presenilins and provide support for the "Ca(2+) hypothesis of AD."

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons

“…This effect is distinct from the other known effects of phosphorylation on both vertebrate and Drosophila LTCCs in which the current-voltage relationships and/or channel activation and inactivation are also affected (77,80). It was suggested recently that presenilin also forms ER Ca 2ϩ leak channels, a function quite distinct from its recognized activity as an intramembranous aspartyl protease (81). In accordance with this model, altered intracellular Ca 2ϩ levels due to the inability of mutant presenilins to conduct Ca 2ϩ properly might affect the tail current via Ca 2ϩ -dependent inactivation of the LTCC.…”

Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells

“…We have recently shown that ␥-secretase activity is essential for adult ␤-cell survival (21). Multiple studies have linked the ␥-secretase-independent presenilin activity to the control of ER Ca 2ϩ release under basal conditions and during caspase-3-mediated apoptosis (53)(54)(55). In general, the presenilin-1 gain-of-function mutations in Alzheimer disease lead to an overload of releasable ER Ca 2ϩ , while presenilin-2 mutations have been reported to decrease Ca 2ϩ stores (56).…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…58 The channels responsible for the passive leak remain to be properly characterized, but there is increasing evidence that presenilins may be leak channels. 45,59 The mutated forms of PS1 that give rise to early-onset FAD reduced the passive leak resulting in enhanced Ca 2+ signals. 59 The mutated PS1 can also interact with the Ins(1,4,5)P 3 R to enhance its sensitivity.…”

“…45,59 The mutated forms of PS1 that give rise to early-onset FAD reduced the passive leak resulting in enhanced Ca 2+ signals. 59 The mutated PS1 can also interact with the Ins(1,4,5)P 3 R to enhance its sensitivity. 60,61 Another important remodeling event associated with AD is a downregulation of the Ca 2+ buffer calbindin D-28k (CB).…”