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

项目总结 铁下垂是最近发现的一种程序性细胞死亡途径，它涉及铁和反应性 氧物种(ROS)。铁下垂不同于细胞凋亡、自噬和其他形式的细胞死亡。当它 最初是在癌症中发现的，现在已经与包括阿尔茨海默氏症在内的几种神经系统疾病有关 疾病(AD)。铁下垂的特征，例如脂质过氧化和铁的失调，早就被观察到了。 阿尔茨海默病患者的大脑样本中。对阿尔茨海默病小鼠模型的遗传学研究也支持阿尔茨海默病在 神经元性死亡中的铁性下垂。因此，显然有必要更好地阐明 在阿尔茨海默病中起作用的上睑下垂。我们最近发现了一种新的调节程序，它可以调节铁上链 癌细胞的细胞死亡。这一途径特别耐人寻味，因为它涉及反义RNA作为基础 材料调节器。我们将这种反义RNA命名为NQO1-AS，因为它是从 阳性链与基因NQO1的3‘非编码区一致。NQO1是一种氧化还原蛋白，我们已经证明 NQO1-AS通过结合和稳定NQO1mRNA来调节细胞的氧化还原状态。更多 重要的是，这个NQO1-AS/NQO1调节轴在铁性下垂中起作用。我们已经证明了沉默 NQO1-AS或NQO1使细胞对氧化应激后的铁链细胞死亡敏感。发现了这一点 为了寻找新的途径，我们询问是否可以在其他生物系统中找到其活性的证据。有意思的, 我们在阿尔茨海默病数据集中观察到NQO1mRNA的表达和稳定性显著降低 从大脑中受这种病理影响最严重的区域。这种减少即使在显微解剖中也持续存在。 样本，这些样本控制一般的神经元丢失。鉴于这些发现，我们认为有很强的理由参与其中 NQO1-NQO1-就像在AD中一样，因此我们已经采取措施将我们对癌细胞的研究扩展到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剖析 NQO1介导的铁性下垂在AD中的可能作用并可能为恢复NQO1提供新的治疗途径 通过模拟NQO1-AS的合成寡聚来激活，并恢复更高的NQO1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.