Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease.
Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease.
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DOI：
10.1111/jcmm.12008
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发表时间：
2013-02
影响因子：
5.3
通讯作者：
Herms J
中科院分区：
文献类型：
--
作者：
Honarnejad K;Jung CK;Lammich S;Arzberger T;Kretzschmar H;Herms J
早老素（PS1和PS2）的突变占早发性家族性阿尔茨海默病病例的绝大多数。早老素作为γ-分泌酶复合物中的催化单位，其参与细胞内钙稳态的调节是近年来阿尔茨海默病研究的热点。在这里，我们报告说，PS1全长全蛋白形式的过度表达，特别是家族性阿尔茨海默病引起的PS1形式，导致显着衰减的钙释放毒胡萝卜素和缓激肽敏感的商店。有趣的是，用γ-分泌酶抑制剂处理HEK 293细胞也导致从内质网（ER）释放的钙的量减少，同时PS1全蛋白水平升高。类似地，PEN-2的敲低（其与PS1内蛋白水解缺陷和其全蛋白形式的积累相关）也导致ER钙释放减少。值得注意的是，我们在携带家族性阿尔茨海默病PS1突变的患者死后的大脑中也检测到了增强的PS1全蛋白水平。总之，全长PS1全蛋白的量增加的条件导致钙从ER释放的减少。基于这些结果，我们提出，扰乱ER钙稳态介导的升高PS1全蛋白水平可能是一个促成因素阿尔茨海默病的发病机制。
Mutations in presenilins (PS1 and PS2) account for the vast majority of early onset familial Alzheimer's disease cases. Beside the well investigated role of presenilins as the catalytic unit in γ-secretase complex, their involvement in regulation of intracellular calcium homeostasis has recently come into more focus of Alzheimer's disease research. Here we report that the overexpression of PS1 full-length holoprotein forms, in particular familial Alzheimer's disease-causing forms of PS1, result in significantly attenuated calcium release from thapsigargin- and bradykinin-sensitive stores. Interestingly, treatment of HEK293 cells with γ-secretase inhibitors also leads to decreased amount of calcium release from endoplasmic reticulum (ER) accompanying elevated PS1 holoprotein levels. Similarly, the knockdown of PEN-2 which is associated with deficient PS1 endoproteolysis and accumulation of its holoprotein form also leads to decreased ER calcium release. Notably, we detected enhanced PS1 holoprotein levels also in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Taken together, the conditions in which the amount of full length PS1 holoprotein is increased result in reduction of calcium release from ER. Based on these results, we propose that the disturbed ER calcium homeostasis mediated by the elevation of PS1 holoprotein levels may be a contributing factor to the pathogenesis of Alzheimer's disease.
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DOI：
10.1016/j.biocel.2012.07.019
发表时间：
2012-11-01
影响因子：
4
作者：
Honarnejad, Kamran;Herms, Jochen
通讯作者：
Herms, Jochen
影响因子：
64.8
作者：
De Strooper, B;Saftig, P;Van Leuven, F
通讯作者：
Van Leuven, F
影响因子：
4.8
作者：
Herms, J;Schneider, I;Van Leuven, F
通讯作者：
Van Leuven, F
DOI：
10.1073/pnas.072033799
发表时间：
2002-04-02
影响因子：
11.1
作者：
Leissring, MA;Murphy, MP;LaFerla, FM
通讯作者：
LaFerla, FM
影响因子：
4
作者：
Jin, Haifeng;Sanjo, Nobuo;Mizusawa, Hidehiro
通讯作者：
Mizusawa, Hidehiro