Redox stress and neuronal functions

多不饱和脂肪酸（PUFA）的非酶促氧化产生了广泛的氧化产物或氧化脂质体，包括许多醛、异前列烷、异缩酮、神经前列烷和4-HNE。这些产品已被广泛检测到在不同的生物体液和组织样本，以证明脂质过氧化和氧化应激。其中，许多成员是亲电的和反应性的，能够修饰蛋白质上的亲核位点以形成稳定的共价加合物。因此，它们被称为反应性脂质物质（RLS）。我们的工作和其他人的工作表明，RLS可以修饰蛋白质的一个子集，称为亲电响应蛋白质组，它协调生物反应，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。一个新出现的概念是，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。这些发现表明，RLS，当存在于低浓度和低于启动细胞死亡所需的，可以作为细胞内介质。然而，目前尚不清楚在哪些条件下RLS代表氧化应激的足迹或细胞功能的介质。我们建议研究温和水平的活性氧（ROS）对RLS的亚细胞形成的影响，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的巯基蛋白。此外，我们将研究轻度星形胶质细胞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.