氧化应激是帕金森病（PD）发病主要机制之一，可导致PD关键蛋白α-synuclein（α-syn）表达增加，但机制未清。SelenoH（SelH）是一种位于细胞核的具抗氧化作用的反式激活因子。课题组发现其在PD小鼠黑质多巴胺神经元中显著上升，且在PD患者外周血细胞中亦有升高。细胞实验显示SelH可受氧化应激诱导，其水平与α-syn表达正相关，并影响细胞存活。那么，SelH是否是氧化应激导致α-syn增加的重要节点？其机制如何？课题组提出假说：机体氧化应激可诱导部分抗氧化蛋白的代偿性上升，包括核SelH。而SelH却通过直接或间接的反式激活作用，上调了α-syn的表达，进而诱导多巴胺神经元渐行性损失和PD的发生。本项目拟在细胞和转基因动物中采用多种生化和分子生物学方法，就上述假说展开深入探索，并分析患者外周血细胞相关指标的变化。研究成果对连通PD的核心发病机制及其干预具有重要的意义。

Oxidative stress, one of the major mechanisms responsible for the pathogenesis of Parkinson’s disease (PD), can up-regulate α-synuclein expression. But the underlying mechanisms remain unclear. SelenoH is a transactivator located in nucleus with antioxidative activity. We found that SelenoH level was significantly increased in dopaminergic neurons of the substantia nigra of PD mice, as well as in peripheral mononuclear cells of PD patients. Our cellular results showed that SelenoH was inducible upon oxidative stress, and was positively associated with the level of α-synuclein, and its overexpression reduced cell viability. Such being the case, is SelenoH a key node between oxidative stress and α-synuclein? By what kind of mechanisms? We herein propose a hypothesis: oxidative stress in body leads to compensatory increases of some antioxidative proteins, which include nuclear SelenoH. However, SelenoH turns to transactivate the expression of α-synuclein through direct or indirect interactions, inducing progressive loss of dopaminergic neurons and PD occurrence. The current project aims to thoroughly study the above hypothesis in cells, animals and transgenic animals applying multiple methods and techniques of biochemistry and molecular biology, and to analyze related changes in mononuclear cells of PD patients. Our results will have great implications in understanding how the PD core mechanisms are connected and the development of potential therapeutic interventions.