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

被引:73
作者
Brunello, Lucia [1 ]
Zampese, Enrico [1 ]
Florean, Cristina [1 ]
Pozzan, Tullio [1 ]
Pizzo, Paola [1 ]
Fasolato, Cristina [1 ]
机构
[1] Univ Padua, Dept Biomed Sci, I-32121 Padua, Italy
关键词
presenilin; calcium stores; Alzheimer's disease; SERCA; aequorin; FAMILIAL ALZHEIMERS-DISEASE; GAMMA-SECRETASE ACTIVITY; MEDIATED SIGNAL-TRANSDUCTION; SINGLE-CHANNEL ACTIVITY; KNOCK-IN MICE; ENDOPLASMIC-RETICULUM; RYANODINE RECEPTOR; CALCIUM HOMEOSTASIS; CORTICAL-NEURONS; LINKED MUTATIONS;
D O I
10.1111/j.1582-4934.2009.00755.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:3358 / 3369
页数:12
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