Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations
Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations
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DOI：
10.1074/jbc.m104096200
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发表时间：
2001-11-16
影响因子：
4.8
通讯作者：
Tohyama, M
中科院分区：
文献类型：
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作者：
Katayama, T;Imaizumi, K;Tohyama, M
最近的研究独立表明，presenifin-1 (PS1) 无效突变体和家族性阿尔茨海默病 (FAD) 相关突变体均应下调未折叠蛋白反应 (UPR) 的信号传导。然而，很难接受这两种突变体对 UPR 具有相同的影响。此外，与这些观察结果相反，PS1 和 PS2 功能的丧失以及 FAD 连接的 PS1 突变体的表达均未报告对 UPR 产生明显影响。因此，需要重新检查和详细分析来阐明PS1功能和UPR信号传导之间的关系。在这里，我们报告 PS1/PS2 无效和显性失活 PS1 突变体（在天冬氨酸残基 257 或 385 处突变）不会影响 UPR 信号传导。相比之下，FAD 连接的 PSI 突变体被证实可以通过抑制 Ire1 α 和 ATF6 的激活来干扰 UPR 信号传导，这两者都是 UPR 中的内质网 (ER) 应激传感器。此外，PS1突变体还干扰了PERK（PKR样ER激酶）的激活，PERK在ER应激期间抑制翻译中发挥着至关重要的作用。总而言之，这些观察结果表明，PS1 突变可能通过功能获得来影响由各个 ER 应激传感器控制的信号通路。
Recent studies have shown independently that presenifin-1 (PS1) null mutants and familial Alzheimer's disease (FAD)-linked mutants should both down-regulate signaling of the unfolded protein response (UPR). However, it is difficult to accept that both mutants possess the same effects on the UPR. Furthermore, contrary to these observations, neither loss of PS1 and PS2 function nor expression of FAD-linked PS1 mutants were reported to have a discernable impact on the UPR. Therefore, re-examination and detailed analyses are needed to clarify the relationship between PS1 function and UPR signaling. Here, we report that PS1/PS2 null and dominant negative PS1 mutants, which are mutated at aspartate residue 257 or 385, did not affect signaling of the UPR. In contrast, FAD-linked PSI mutants were confirmed to disturb UPR signaling by inhibiting activation of both Ire1 alpha and ATF6, both of which are endoplasmic reticulum (ER) stress transducers in the UPR. Furthermore, PS1 mutants also disturbed activation of PERK (PKR-like ER kinase), which plays a crucial role in inhibiting translation during ER stress. Taken together, these observations suggested that PS1 mutations could affect signaling pathways controlled by each of the respective ER-stress transducers, possibly through a gain-of-function.