Presenilins Function as ER Calcium Leak Channels: Implications for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) cases in which a genetic cause has been identified. FAD mutations and genetic deletions of presenilins have been linked with calcium (Ca2+) signaling abnormalities, but mechanistic basis for these results has not been clearly determined. Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase. In our studies we discovered that in addition to acting as a gamma-secretase, presenilins also function as passive endoplasmic reticulum calcium (Ca2+) leak channels. We demonstrate that wild type PS1 and PS2 proteins 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 discovered that presenilins account for ∼80% of passive Ca2+ leak from the endoplasmic reticulum. The ER Ca2+ leak function of presenilins is independent from their gamma-secretase function In additional experiments we demonstrated that ER Ca2+ leak function of presenilins is impaired by M146V, L166P, A246E, E273A, G384A and P436Q FAD mutations in PS1 and N141I mutation in PS2. In contrast, FTD-associated mutations (L113P, G183V and Rins352) did not appear to affect ER Ca2+ leak function of PS1 in our experiments, indicating that the observed effects are disease-specific. Our data uncover a novel Ca2+ signaling function of presenilins and provide support to the potential role of disturbed Ca2+ homeostasis in AD pathogenesis. We are in the process of expanding these findings to neuronal system. Our latest findings will be discussed.