Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress
Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress
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DOI：
10.3233/jad-2010-1360
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Mizusawa, Hidehiro
中科院分区：
文献类型：
--
作者：
Jin, Haifeng;Sanjo, Nobuo;Mizusawa, Hidehiro
早老素-1 （PSEN1）是γ -分泌酶复合物的主要成分，其全蛋白和内溶蛋白片段的总水平受到严格调控。我们研究了几种内质网（ER）应激对PSEN1 mRNA、全蛋白和片段水平定量变化的影响。将内质网应激诱导化合物tunicamycin、brefeltin - a、thapsigargin和staurosporine添加到各种人细胞系的培养基中。Tunicamycin处理导致HEK293细胞中PSEN1全蛋白产量增加一倍，在GOTO人神经母细胞瘤和KNS-42人胶质瘤细胞系中，全蛋白产量增加约180%，而PSEN1 N端或c端片段的数量没有改变。HEK293细胞中全蛋白水平的升高伴随着PSEN1 mRNA表达的增加。稳定过表达PSEN1全蛋白的HEK293细胞对tunicamycin诱导的内质网应激的抵抗能力增强，但对sarco ER钙- atp酶（SERCA）特异性抑制剂thapsigargin引起的内质网应激没有抵抗能力。在tunicamycin诱导内质网应激的野生型HEK293细胞中，SERCA与PSEN1全蛋白相互作用的量增加。PSEN1的产生因细胞类型和环境而异。结果表明，该全蛋白与SERCA通道形成复合物，参与细胞内钙稳态的调节。这些发现为阿尔茨海默病的钙假说提供了支持。
Presenilin-1 (PSEN1) is a primary component of the gamma-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease.