核SelenoH对氧化应激诱导的α-synuclein表达及对帕金森病发病的调控作用研究

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.

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。

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表达增加，但机制未清。课题组前期的数据表明SELENOH可能是氧化应激导致α-synuclein增加的重要节点。本项目旨在阐明SELENOH调控α-synuclein表达作用和机制，以及对PD易感性的影响。本项目采用多种生物化学和分子生物学等方法，在细胞和动物以及PD病人外周血细胞中进行了研究。研究结果发现：1）细胞水平、动物水平以及PD患者中均确定PD中SELENOH表达水平上升；2）SELENOH可能通过抑制Parkin参与的泛素-蛋白酶体途径增加细胞中α-synuclein 蛋白水平；3）在PD发病的早期，SELENOH可能可以促进PD的发生；4）SELENOH对小鼠大脑皮层和小脑的发育具有重要调控作用。总之，本项目的研究结果表明了SELENOH与PD发病相关，对连通PD的核心发病机制及其干预具有重要的意义。同时，神经发育相关的新发现也为后续SELENOH蛋白功能的研究提供了重要基础。