Redox stress and neuronal functions

多不饱和脂肪酸(PUFAs)的非酶氧化产生了广泛的氧化产物或氧化脂体，包括许多醛、异前列腺素、异酮、神经前列腺素和4-HNE。这些产物在不同的生物液和组织样本中被广泛检测到，以证明脂质过氧化和氧化应激。其中，许多分子是亲电性和反应性的，能够修饰蛋白质上的亲核位点，形成稳定的共价加合物。因此，它们被称为反应性脂质物种(RLS)。我们和其他人的工作表明，RLS可以修饰一组蛋白质，称为电泳性反应蛋白质组，它协同协调生物反应，如与信号转导、线粒体呼吸和细胞死亡或生存途径相关的蛋白质。一个新的概念是，低水平的内源性RLS可能有助于调节细胞活动，如线粒体和细胞核之间的逆行信号传递。这些发现表明，当RLS存在于低浓度或低于启动细胞死亡所需的浓度时，可以发挥细胞内介质的作用。然而，目前还不清楚在哪些情况下RLS代表了氧化应激的足迹，或者是细胞功能的中介。我们建议研究轻度水平的ROS对RLS亚细胞形成的影响，并分析RLS对蛋白质翻译后修饰的影响，特别是对神经元和神经胶质细胞中硫醇蛋白的影响。此外，我们还将研究轻度星形细胞RLS对神经元功能的影响。总之，我们的研究将有助于阐明RLS在细胞内水平上的作用及其对神经元活动的作用。

The non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs) produced a broad range of oxidation products or oxylipidome including many aldehydes, isoprostanes, isoketals, neuroprostanes, and 4-HNE. These products have been widely detected in different biological fluids and tissue samples to evidence lipoperoxidation and oxidative stress. Among them, many members are electrophilic and reactive, capable of modifying nucleophilic sites on proteins to form stable covalent adducts. They are, therefore, called the reactive lipid species (RLS). Our work and others showed that RLS can modify a subset of proteins, called the electrophile-reponsive proteome, which, in concert orchestrate biological response such as proteins associated with signal transduction, mitochondrial respiration and cell death or survival pathways. A new emerging concept is that low levels of endogenous RLS could contribute to the regulation of cellular activities such as the retrograde signaling between mitochondria and the nucleus. These findings suggest that the RLS, when present at low concentrations and below that required to initiate cell death, can behave as intracellular mediators. However, it is not clear in which conditions RLS represent the footprints of oxidative stress or are mediators of cellular functions. We propose to study the effects of mild levels of reactive oxygen species (ROS) on the subcellular formation of RLS and to analyze the effects of RLS on post-translational modification of proteins and particularly on thiols proteins in neuronal and glial cells. Moreover, we will investigate the effects of mild level of astrocytic RLS on neuronal functions. In conclusion, our study will help to elucidate the role of RLS at the intracellular levels and their role on neuronal activity.