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 journalArticle

473 Scopus citations

Abstract

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
JournalCell
Volume126
Issue number5
DOIs
StatePublished - Sep 8 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S. F., Hao, Y. H., Serneels, L., De Strooper, B., Yu, G., & Bezprozvanny, I. (2006). Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Cell, 126(5), 981-993. https://doi.org/10.1016/j.cell.2006.06.059