Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations
Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations
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DOI：
10.1016/j.cell.2006.06.059
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发表时间：
2006-09-08
期刊：
影响因子：
64.5
通讯作者：
Bezprozvanny, Ilya
中科院分区：
文献类型：
--
作者：
Tu, Huiping;Nelson, Omar;Bezprozvanny, Ilya
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for similar to 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 similar to 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 gamma-secretase activity. Our data suggest a Ca2+ signaling function for presenilins and provide support for the "Ca2+ hypothesis of AD".
