Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations.
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."
Tu
Huiping
H
Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Nelson
Omar
O
Bezprozvanny
Arseny
A
Wang
Zhengnan
Z
Lee
Sheu-Fen
SF
Hao
Yi-Heng
YH
Serneels
Lutgarde
L
De Strooper
Bart
B
Yu
Gang
G
Bezprozvanny
Ilya
I
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts; D006706:Homeostasis; D008051:Lipid Bilayers; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D015220:Calcium Channels; D008051:Lipid Bilayers; D053764:Presenilin-1; D053766:Presenilin-2; D011994:Recombinant Proteins; D002118:Calcium