Alzheimer's Administrative Supplement - An antisense RNA-mediated regulatory program that drives cancer metastasis

项目摘要 铁凋亡是最近发现的程序性细胞死亡的途径，其涉及铁和反应性细胞凋亡。 氧物种（ROS）。铁凋亡不同于细胞凋亡、自噬和其他形式的细胞死亡。虽然 最初是在癌症中发现的，现在它与几种神经系统疾病有关，包括阿尔茨海默氏症 疾病（AD）。铁下垂的特征，例如脂质过氧化和铁失调，早已被观察到 AD患者的大脑样本在AD小鼠模型中的遗传研究也支持了 神经元死亡中的铁凋亡。因此，显然需要更好地阐明 在AD中起作用的铁凋亡。我们最近发现了一种新的调节程序， 癌细胞的死亡。这种途径特别有趣，因为它涉及反义RNA作为潜在的 主调节器。我们将这种反义RNA命名为NQO 1-AS，因为它是从启动子转录的。 与基因NQO 1的3 'UTR一致的正链。NQO 1是一种氧化还原蛋白，我们已经证明， NQO 1-AS通过结合和稳定NQO 1 mRNA来调节细胞的氧化还原状态。更 重要的是，该NQO 1-AS/NQO 1调节轴在铁凋亡中起作用。我们已经证明沉默 NQO 1-AS或NQO 1使细胞对氧化应激后的铁凋亡细胞死亡敏感。在发现了这一点之后 新途径，我们问是否可以在其他生物系统中找到其活性的证据。有意思， 我们观察到阿尔茨海默病数据集中NQO 1 mRNA表达和稳定性显著降低， 大脑中受这种病理影响最大的区域。这种减少甚至在显微解剖的 样品，其控制一般神经元损失。鉴于这些发现，我们看到了一个强有力的证据， NQO 1-NQO 1-AS在AD中的作用，因此我们已经采取措施将我们在癌细胞中的研究扩展到iPSC， 阿尔茨海默病模型中的衍生神经元。这项研究的成功完成将解剖 NQO 1介导的铁凋亡在AD中的可能作用，并可能提供新的治疗途径， 通过模拟NQO 1-AS并恢复更高的NQO 1活性的合成寡核苷酸来提高NQO 1活性。

PROJECT SUMMARY Ferroptosis is a recently discovered pathway of programmed cell death, which involves iron and reactive oxygen species (ROS). Ferroptosis is distinct from apoptosis, autophagy and other forms of cell death. While it was first discovered in cancer, it has now been implicated in several neurologic diseases, including Alzheimer's disease (AD). Hallmarks of ferroptosis, e.g. lipid peroxidation and iron dysregulation, have long been observed in brain samples from AD patients. Genetic studies in mouse models of AD also support a substantial role for ferroptosis in neuronal death. Therefore, there is a clear need for better elucidating the regulatory pathways of ferroptosis that play a role in AD. We recently discovered a new regulatory program that modulates ferroptotic cell death in cancer cells. This pathway is especially intriguing as it involves an antisense RNA as the underlying mater regulator. We have names this antisense RNA NQO1-AS as it is transcribed from a promoter on the positive strand coinciding with the 3'UTR of gene NQO1. NQO1 is a redox protein and we have shown that the NQO1-AS modulates the redox state of the cell through binding and stabilization of the NQO1 mRNA. More importantly, this NQO1-AS/NQO1 regulatory axis plays a role in ferroptosis. We have shown that silencing NQO1-AS or NQO1 sensitizes cells to ferroptotic cell death following oxidative stress. Having discovered this new pathway, we asked whether evidence of its activity could be found in other biological systems. Interesting, we observed a significant reduction in NQO1 mRNA expression and stability in Alzheimer's disease datasets from the regions of the brain most affected by this pathology. This reduction persisted even in microdissected samples, which control for general neuronal loss. Given these findings, we see a strong case for the involvement of the NQO1-NQO1-AS in AD, and therefore we have taken steps to extend our studies in cancer cells to iPSC- derived neurons in models of Alzheimer's disease. The successful completion of this study will dissect the possible role of NQO1-mediated ferroptosis in AD and may provide new therapeutic pathways that restore NQO1 activity through synthetic oligos that mimic NQO1-AS and restore higher NQO1 activity.