Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease.
Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease.
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氧化应激对 HRD1（一种与阿尔茨海默病有关的泛素连接酶）溶解度的影响。
DOI：
10.1371/journal.pone.0094576
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Nomura Y
中科院分区：
文献类型：
--
作者：
Saito R;Kaneko M;Kitamura Y;Takata K;Kawada K;Okuma Y;Nomura Y
E3泛素连接酶HRD 1存在于脑神经元的内质网膜中，并参与内质网相关的降解。我们先前证实，神经元中HRD 1表达的抑制导致淀粉样前体蛋白的积累，导致与内质网应激和细胞凋亡相关的淀粉样β蛋白的产生。此外，HRD 1水平在阿尔茨海默病患者的大脑皮层中显著降低，因为其不溶性。影响HRD 1溶解度的机制尚未完全了解。我们发现HRD 1蛋白不被氧化应激所溶解，但不被其他阿尔茨海默病相关分子和应激源，如淀粉样蛋白β、tau蛋白和内质网应激所溶解。此外，我们提出了这样的可能性：4-羟基-2-壬烯醛（一种氧化应激标记物）对HRD 1的修饰降低了HRD 1蛋白的溶解度，并且氧化应激导致HRD 1积累到攻击性基因组中。因此，氧化应激诱导的HRD 1不溶解可能参与阿尔茨海默病发病机制中淀粉样蛋白β产生增加和淀粉样蛋白β诱导的氧化应激的恶性循环。
The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane of brain neurons and is involved in endoplasmic reticulum-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid β production associated with endoplasmic reticulum stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer’s disease patients because of its insolubility. The mechanisms that affect HRD1 solubility are not well understood. We here show that HRD1 protein was insolubilized by oxidative stress but not by other Alzheimer’s disease-related molecules and stressors, such as amyloid β, tau, and endoplasmic reticulum stress. Furthermore, we raise the possibility that modifications of HRD1 by 4-hydroxy-2-nonenal, an oxidative stress marker, decrease HRD1 protein solubility and the oxidative stress led to the accumulation of HRD1 into the aggresome. Thus, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased amyloid β production and amyloid β-induced oxidative stress in Alzheimer’s disease pathogenesis.
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影响因子：
7.8
作者：
Hitomi, Junichi;Katayama, Taiichi;Eguchi, Yutaka;Kudo, Takashi;Taniguchi, Manabu;Koyama, Yoshihisa;Manabe, Takayuki;Yamagishi, Satoru;Bando, Yoshio;Imaizumi, Kazunori;Tsujimoto, Yoshihide;Tohyama, Masaya
通讯作者：
Tohyama, Masaya
影响因子：
30.8
作者：
MULLAN, M;CRAWFORD, F;LANNFELT, L
通讯作者：
LANNFELT, L
影响因子：
4.8
作者：
GREGORI, L;FUCHS, C;GOLDGABER, D
通讯作者：
GOLDGABER, D
影响因子：
3.7
作者：
Lee, Hyun-Pil;Pancholi, Neel;Lee, Hyoung-gon
通讯作者：
Lee, Hyoung-gon
影响因子：
2.5
作者：
Drake, J;Petroze, R;Butterfield, DA
通讯作者：
Butterfield, DA