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

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for ∼40% of familial AD (FAD) cases. FAD mutations and genetic deletions of presenilins have been associated with calcium (Ca²⁺) 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 ∼80% of passive Ca²⁺ leak from the endoplasmic reticulum. Deficient Ca²⁺ 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 Ca²⁺ leak function of presenilins is independent of their γ-secretase activity. Our data suggest a Ca²⁺ signaling function for presenilins and provide support for the "Ca²⁺ hypothesis of AD.".