title: Up-regulation of inositol 1,4,5-trisphosphate receptor type 1 is responsible for a decreased endoplasmic-reticulum Ca2+ content in presenilin double knock-out cells.
abstract: Presenilins (PS) are proteins involved in the pathogenesis of autosomal-dominant familial cases of Alzheimer's disease. Mutations in PS are known to induce specific alterations in cellular Ca2+ signaling which might be involved in the pathogenesis of neurodegenerative diseases. Mouse embryonic fibroblasts (MEF) deficient in PS1 and PS2 (PS DKO) as well as the latter rescued with PS1 (Rescue), were used to investigate the underlying mechanism of these alterations in Ca2+ signaling. PS DKO cells were characterized by a decrease in the [Ca2+]ER as measured by ER-targeted aequorin luminescence and an increased level of type 1 inositol 1,4,5-trisphosphate receptor (IP3R1). The lower [Ca2+]ER was associated with an increase in a Ca2+ leak from the ER. The increased IP3R1 expression and the concomitant changes in ER Ca2+ handling were reversed in the Rescue cells. Moreover using RNA-interference mediated reduction of IP3R1 we could demonstrate that the up-regulation of this isoform was responsible for the increased Ca2+ leak and the lowered [Ca2+]ER PS DKO cells. Finally, we show that the decreased [Ca2+]ER in PS DKO cells was protective against apoptosis.
authors: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors: Nael Nadif
authors: NN
authors: Kasri
authors: Sarah L
authors: SL
authors: Kocks
authors: Leen
authors: L
authors: Verbert
authors: Sébastien S
authors: SS
authors: Hébert
authors: Geert
authors: G
authors: Callewaert
authors: Jan B
authors: JB
authors: Parys
authors: Ludwig
authors: L
authors: Missiaen
authors: Humbert
authors: H
authors: De Smedt