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

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...

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Main Authors:	Brunello, Lucia, Zampese, Enrico, Florean, Cristina, Pozzan, Tullio, Pizzo, Paola, Fasolato, Cristina
Format:	Online
Language:	English
Published:	John Wiley & Sons, Ltd 2009
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516491/

id	pubmed-4516491
recordtype	oai_dc
spelling	pubmed-45164912015-08-03 Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake Brunello, Lucia Zampese, Enrico Florean, Cristina Pozzan, Tullio Pizzo, Paola Fasolato, Cristina Articles 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. John Wiley & Sons, Ltd 2009-09 2009-03-27 /pmc/articles/PMC4516491/ /pubmed/19382908 http://dx.doi.org/10.1111/j.1582-4934.2009.00755.x Text en © 2009 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Brunello, Lucia Zampese, Enrico Florean, Cristina Pozzan, Tullio Pizzo, Paola Fasolato, Cristina
spellingShingle	Brunello, Lucia Zampese, Enrico Florean, Cristina Pozzan, Tullio Pizzo, Paola Fasolato, Cristina Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake
author_facet	Brunello, Lucia Zampese, Enrico Florean, Cristina Pozzan, Tullio Pizzo, Paola Fasolato, Cristina
author_sort	Brunello, Lucia
title	Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake
title_short	Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake
title_full	Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake
title_fullStr	Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake
title_full_unstemmed	Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake
title_sort	presenilin-2 dampens intracellular ca2+ stores by increasing ca2+ leakage and reducing ca2+ uptake
description	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.
publisher	John Wiley & Sons, Ltd
publishDate	2009
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516491/
_version_	1613252727598481408

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

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