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

Huiping Tu, Omar Nelson, Arseny Bezprozvanny, Zhengnan Wang, Sheu Fen Lee, Yi Heng Hao, Lutgarde Serneels, Bart De Strooper, Gang Yu, Ilya Bezprozvanny

Research output: Contribution to journalArticlepeer-review

495 Scopus citations


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.".

Original languageEnglish (US)
Pages (from-to)981-993
Number of pages13
Issue number5
StatePublished - Sep 8 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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