Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1.
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 gamma-secretase. Recently, we discovered that presenilins also function as passive ER Ca(2+) leak channels. Here we used planar lipid bilayer reconstitution assays and Ca(2+) imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca(2+) 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 Ca(2+) leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca(2+) leak function of PS1 in our experiments. We validated our findings in Ca(2+) 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 Ca(2+) 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 Ca(2+) homeostasis in Alzheimer disease pathogenesis.
Nelson
Omar
O
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Tu
Huiping
H
Lei
Tianhua
T
Bentahir
Mostafa
M
de Strooper
Bart
B
Bezprozvanny
Ilya
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology; D018411:Spodoptera
D015220:Calcium Channels; D053764:Presenilin-1