Molecular mechanism of the qualify control of proteins

在这项研究中，我们研究了内质网（ER）应激在家族性和散发性阿尔茨海默病（AD）中的作用。结果表明，家族性AD相关的早老素-1 （PS1）突变诱导了对内质网应激的脆弱性，并且在散发性AD患者大脑中观察到的早老素-2 （PS2）剪接变异之一（PS2V）也导致了对内质网应激的脆弱性。进一步研究表明，缺氧、金属等引起的羟基自由基诱导HMGAla蛋白产生异常剪接变异（PS2V）。这些结果提示抑制HMGAla蛋白是治疗散发性AD的新方法。接下来，我们研究了内质网应激下的凋亡途径，发现caspase-4介导内质网应激诱导的-和β-淀粉样蛋白诱导的人细胞凋亡信号通路。这些结果提示内质网应激和caspase-4参与了AD细胞死亡。因此，我们研究了caspase-4在家族性ad相关的PS1突变中的激活（ΔE9）。ER胁迫下caspase-4的裂解通过家族AD相关突变的过表达而增强（ΔE9），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的过表达诱导了caspase-9和caspase-3的分裂，而没有从线粒体中释放细胞色素c。这些结果也提示，调节活化的caspase-4可能是治疗AD的新方法之一。

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.