Familial Alzheimer disease-linked mutations specifically disrupt Ca 2+ leak function of presenilin 1

Omar Nelson, Huiping Tu, Tianhua Lei, Mostafa Bentahir, Bart De Strooper, Ilya Bezprozvanny

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1230-1239
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number5
DOIs
StatePublished - May 1 2007

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Presenilin-1
Presenilins
Alzheimer Disease
Mutation
Dementia
Fibroblasts
Amyloid Precursor Protein Secretases
Lipid Bilayers
Homeostasis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Familial Alzheimer disease-linked mutations specifically disrupt Ca 2+ leak function of presenilin 1. / Nelson, Omar; Tu, Huiping; Lei, Tianhua; Bentahir, Mostafa; De Strooper, Bart; Bezprozvanny, Ilya.

In: Journal of Clinical Investigation, Vol. 117, No. 5, 01.05.2007, p. 1230-1239.

Research output: Contribution to journalArticle

Nelson, Omar ; Tu, Huiping ; Lei, Tianhua ; Bentahir, Mostafa ; De Strooper, Bart ; Bezprozvanny, Ilya. / Familial Alzheimer disease-linked mutations specifically disrupt Ca 2+ leak function of presenilin 1. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 5. pp. 1230-1239.
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