Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression
Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression
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DOI：
10.1038/35046500
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发表时间：
2000-12
影响因子：
21.3
通讯作者：
N. Sato;F. Urano;J. Leem;Seong‐Hun Kim;Mingqing Li;D. Donoviel;A. Bernstein;Amy S. Lee;D. Ron;M. Veselits;S. Sisodia;G. Thinakaran
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文献类型：
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作者：
N. Sato;F. Urano;J. Leem;Seong‐Hun Kim;Mingqing Li;D. Donoviel;A. Bernstein;Amy S. Lee;D. Ron;M. Veselits;S. Sisodia;G. Thinakaran
早老素1（PS1）是一种多位性膜蛋白，在一组选定的跨膜蛋白的运输和蛋白水解中起关键作用。绝大多数患有早发性家族性阿尔茨海默病（FAD）的个体在PS1中携带错义突变。两项研究表明，PS1功能的丧失，或FAD连锁的PS1变体的表达，损害了哺乳动物的未折叠蛋白反应（UPR），我们试图评估PS1在哺乳动物UPR中的潜在作用。在这里，我们表明，无论是内质网（ER）应激诱导的BiP和CHOP信使RNA的积累，也不是ER应激激酶IRE1α和PERK的激活，是在细胞缺乏PS1和PS2或在细胞表达FAD连接的PS1变体受到损害。我们还表明，BiP的水平是没有显着不同的个体的大脑中散发性阿尔茨海默氏病或PS1介导的FAD控制大脑中的水平。我们的研究结果提供了证据表明，无论是PS1和PS2功能的丧失，还是PS1变体的表达，都不会对ER应激介导的UPR通路的几个已建立的读出的诱导产生明显的影响。
Presenilin 1 (PS1), a polytopic membrane protein, has a critical role in the trafficking and proteolysis of a selected set of transmembrane proteins. The vast majority of individuals affected with early onset familial Alzheimer's disease (FAD) carry missense mutations in PS1. Two studies have suggested that loss of PS1 function, or expression of FAD-linked PS1 variants, compromises the mammalian unfolded-protein response (UPR), and we sought to evaluate the potential role of PS1 in the mammalian UPR. Here we show that that neither the endoplasmic reticulum (ER) stress-induced accumulation of BiP and CHOP messenger RNA, nor the activation of ER stress kinases IRE1α and PERK, is compromised in cells lacking both PS1 and PS2 or in cells expressing FAD-linked PS1 variants. We also show that the levels of BiP are not significantly different in the brains of individuals with sporadic Alzheimer's disease or PS1-mediated FAD to levels in control brains. Our findings provide evidence that neither loss of PS1 and PS2 function, nor expression of PS1 variants, has a discernable impact on ER stress-mediated induction of the several establishedreadouts' of the UPR pathway.