Neurotoxic mechanisms triggered by Alzheimer's disease‐linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target
Neurotoxic mechanisms triggered by Alzheimer's disease‐linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target
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阿尔茨海默病相关突变体 M146L 早老素 1 触发的神经毒性机制：通过新型百日咳毒素靶点参与 NO 合酶
DOI：
10.1046/j.0022-3042.2001.00722.x
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发表时间：
2002
影响因子：
4.7
通讯作者：
I. Nishimoto
中科院分区：
文献类型：
--
作者：
Y. Hashimoto;Y. Ito;Erika Arakawa;Y. Kita;K. Terashita;T. Niikura;I. Nishimoto
虽然有报道称，家族性阿尔茨海默病（FAD）相关的淀粉样前体蛋白（APP）和早老素（PS）2突变体以对抗氧化剂和百日毒（PTX）敏感的方式诱导神经元细胞毒性，但PS1介导的神经元细胞死亡机制尚不清楚。我们之前发现，使用具有蜕皮激素控制表达系统的神经元细胞，两种FAD相关的APP突变体的细胞毒性具有多种机制，但细节不同。在这里，我们报告了该系统显示：(i) FAD关联的M146L‐PS1的低表达导致神经元细胞死亡，而野生型（wt）PS1的低表达则不会导致神经元细胞死亡；（ii） M146L‐PS1突变特异性细胞毒性对抗氧化剂谷胱甘肽乙酯敏感，对Ac‐DEVD‐CHO有抗性；（iii）高表达wtPS1的细胞毒性对两者均有抗性；（iv） PTX抑制M146L‐PS1的细胞毒性。也很可能涉及的超氧化物生成酶是一氧化氮合酶（NOS），并且M146L - PS1对PTX敏感的细胞毒性信号不是由Gi/o蛋白介导的。我们得出结论，M146L‐PS1通过一个新的PTX靶点激活NOS介导的细胞毒性途径。
While it has been reported that familial Alzheimer's disease (FAD)‐linked mutants of amyloid precursor protein (APP) and presenilin (PS)2 induce neuronal cytotoxicity in a manner sensitive to antioxidant and pertussis toxin (PTX), little of the mechanism for PS1‐mediated neuronal cell death has been characterized. We previously found that multiple mechanisms, different in detail, underlie cytotoxicities by two FAD‐linked mutants of APP, using neuronal cells with an ecdysone‐controlled expression system. Here we report that this system revealed that (i) low expression of FAD‐linked M146L‐PS1 caused neuronal cell death, whereas that of wild‐type (wt)PS1 did not; (ii) mutation‐specific cytotoxicity by M146L‐PS1 was sensitive to antioxidant glutathione‐ethyl‐ester and resistant to Ac‐DEVD‐CHO; (iii) cytotoxicity by higher expression of wtPS1 was resistant to both; and (iv) cytotoxicity by M146L‐PS1 was inhibited by PTX. It was also highly likely that the involved superoxide‐generating enzyme was nitric oxide synthase (NOS), and that the PTX‐sensitive cytotoxic signal by M146L‐PS1 was mediated by none of the Gi/o proteins. We conclude that M146L‐PS1 activates a NOS‐mediated cytotoxic pathway via a novel PTX target.
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影响因子：
1.7
作者：
Guo, Q;Furukawa, K;MAttson, MP
通讯作者：
MAttson, MP
影响因子：
64.8
作者：
Nakagawa, T;Zhu, H;Yuan, JY
通讯作者：
Yuan, JY
影响因子：
64.8
作者：
GOATE, A;CHARTIERHARLIN, MC;HARDY, J
通讯作者：
HARDY, J
DOI：
10.1073/pnas.101133498
发表时间：
2001-05-22
影响因子：
11.1
作者：
Hashimoto, Y;Niikura, T;Nishimoto, I
通讯作者：
Nishimoto, I
影响因子：
5.3
作者：
Hashimoto, Y;Niikura, T;Nishimoto, I
通讯作者：
Nishimoto, I