Effects of Oxidative Stress on the Solubility of HRD1, a Ubiquitin Ligase Implicated in Alzheimer's Disease.

E3泛素连接酶Hrd1存在于脑神经元的内质网膜中，参与内质网相关的降解。我们先前证明，抑制神经元中Hrd1的表达会导致淀粉样前体蛋白的积聚，导致与内质网应激和细胞凋亡相关的淀粉样β蛋白(Abeta)的产生。此外，由于阿尔茨海默病(AD)患者大脑皮层中Hrd1的不溶性，Hrd1水平显著降低。影响Hrd1溶解度的机理还不是很清楚。我们在这里表明，Hrd1蛋白被氧化应激所不溶解。此外，我们发现，4-羟基-2-壬烯醛修饰Hrd1降低了Hrd1的溶解度，氧化应激导致Hrd1积聚到侵袭体中。因此，氧化应激诱导的Hrd1不溶化可能参与了AD发病机制中Abeta生成增加和Abeta诱导的氧化应激的恶性循环。

The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane (ER) of brain neurons and is involved in ER-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid beta (Abeta) production associated with ER stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer's disease (AD) 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. Furthermore, we reveal that modifications of HRD1 by 4-hydroxy-2-nonenal decreases HRD1 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 Abeta production and Abeta-induced oxidative stress in AD pathogenesis.