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Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake

Authors
  • Brunello, Lucia
  • Zampese, Enrico
  • Cristina Florean
  • Pozzan, Tullio
  • Pizzo, Paola
  • Fasolato, Cristina
Type
Published Article
Journal
Journal of Cellular and Molecular Medicine
Publisher
Wiley (Blackwell Publishing)
Publication Date
Mar 27, 2009
Volume
13
Issue
9b
Pages
3369–3369
Identifiers
DOI: 10.1111/j.1582-4934.2009.00755.x
Source
LBMCC
Keywords
License
Green

Abstract

We have previously shown that familial Alzheimer’s disease mutants of presenilin-2 (PS2) and, to a lesser extent, of presenilin-1 (PS1) lower the Ca2+ concentration of intracellular stores. We here examined the mechanism by which wild-type and mutant PS2 affect store Ca2+ handling. By using HeLa, SH-SY5Y and MEFs as model cells, and recombinant aequorins as Ca2+ probes, we show evidence that transient expression of either wild-type or mutant PS2 increases the passive Ca2+ leakage: both ryanodine- and IP3-receptors contribute to Ca2+ exit out of the ER, whereas the ribosome translocon complex is not involved. In SH-SY5Y cells and MEFs, wild-type and mutant PS2 potently reduce the uptake of Ca2+ inside the stores, an effect that can be counteracted by over-expression of SERCA-2B. On this line, in wild-type MEFs, lowering the endogenous level of PS2 by RNA interference, increases the Ca2+-loading capability of intracellular stores. Furthermore, we show that in PS double knockout MEFs, reduction of Ca2+ stores is mimicked by the expression of PS2-D366A, a loss-of-function mutant, uncleaved because also devoid of presenilinase activity but not by co-expression of the two catalytic active fragments of PS2. In summary, both physiological and increased levels of wild-type and mutant PS2 reduce the Ca2+ uptake by intracellular stores. To exert this newly described function, PS2 needs to be in its full-length form, even if it can subsequently be cleaved.

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