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Cell. 2006 Sep 8;126(5):981-93.

Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations.

Author information

1
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

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."

PMID:
16959576
PMCID:
PMC3241869
DOI:
10.1016/j.cell.2006.06.059
[Indexed for MEDLINE]
Free PMC Article

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