Molecular mechanism of the qualify control of proteins

在这项研究中，我们研究了参与内质网（ER）应激在家族性和散发性阿尔茨海默病（AD）。结果表明，家族性AD连锁早老素-1（PS1）突变可诱导对ER应激的脆弱性，而在散发性AD患者脑中观察到的早老素-2（PS2）剪接变体（PS2 V）也可导致对ER应激的脆弱性。进一步的研究表明，由缺氧、金属等引起的羟基自由基诱导HMGAla蛋白，导致异常剪接变体（PS2 V）。这些结果提示抑制HMGAla蛋白作为散发性AD的新疗法。接下来，我们研究了ER应激下的凋亡途径，发现caspase-4介导了人细胞中ER应激诱导的和β-淀粉样蛋白诱导的凋亡信号传导。这些结果表明ER应激和caspase-4参与AD中观察到的细胞死亡。因此，我们研究了家族性AD连锁PS1突变（ΔE9）中caspase-4的激活。在ER应激下，家族性AD连锁突变（ΔE9）的过表达增强了caspase-4的切割，表明caspase-4是参与AD凋亡信号传导的关键caspase。我们还发现，caspase-4的过度表达诱导caspase-9和caspase-3的切割，而不释放细胞色素C从线粒体。这些结果也表明，活化的caspase-4的调节可能是AD的新疗法之一。

In this research, we examined the involvement of to the endoplasmic reticulum (ER) stress in both familial and sporadic Alzheimer's disease (AD). As the resulrts, we showed that familial AD-linked presenilin-1 (PS1) mutation induced the fragility to the ER stress and that one of the presenilin-2 (PS2) splice valiants (PS2V), which were observed in the sporadic AD patient brains, also caused the fragility to the ER stress. Further studies elucidated that hydroxy radicals caused by hypoxia, metals, etc. induced HMGAla protein resulting in the aberrant splicing variant (PS2V). These results suggest the inhibition of HMGAla protein as the new therapy for sporadic AD. Next, we investigated the apoptosis pathway under the ER stress and found that caspase-4 mediates ER stress induced- and β-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. Thus, we studied the activation of caspase-4 in the familial AD-linked PS1 mutation (ΔE9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (ΔE9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. These results also suggest that the regulation of activated caspase-4 should be one of the new therapies for AD.