TY - JOUR
T1 - Familial Alzheimer disease-linked mutations specifically disrupt Ca 2+ leak function of presenilin 1
AU - Nelson, Omar
AU - Tu, Huiping
AU - Lei, Tianhua
AU - Bentahir, Mostafa
AU - De Strooper, Bart
AU - Bezprozvanny, Ilya
PY - 2007/5/1
Y1 - 2007/5/1
N2 - Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by γ-secretase. Recently, we discovered that presenilins also function as passive ER Ca2+ leak channels. Here we used planar lipid bilayer reconstitution assays and Ca 2+ imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca2+ leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca2+ leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca2+ leak function of PS1 in our experiments. We validated our findings in Ca2+ imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca2+ leak activity. In contrast, none of the FTD-associated mutations affected ER Ca 2+ leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca2+ homeostasis in Alzheimer disease pathogenesis.
AB - Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by γ-secretase. Recently, we discovered that presenilins also function as passive ER Ca2+ leak channels. Here we used planar lipid bilayer reconstitution assays and Ca 2+ imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca2+ leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca2+ leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca2+ leak function of PS1 in our experiments. We validated our findings in Ca2+ imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca2+ leak activity. In contrast, none of the FTD-associated mutations affected ER Ca 2+ leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca2+ homeostasis in Alzheimer disease pathogenesis.
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U2 - 10.1172/JCI30447
DO - 10.1172/JCI30447
M3 - Article
C2 - 17431506
AN - SCOPUS:34248185927
SN - 0021-9738
VL - 117
SP - 1230
EP - 1239
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -