DJ-1 function and oxidative stress

DJ-1突变是隐性帕金森症的一种非常罕见的原因，在世界范围内占少数病例。 尽管精确的分子功能尚不清楚，但几个实验室已经证明所涉及的蛋白质参与氧化应激反应。 在细胞水平上，DJ-1缺失的影响之一是线粒体功能受损。 这可能与氧化应激有关，因为线粒体是活性氧（ROS）的主要来源，尽管这是不确定的。 在过去的几年中，我们已经确定了DJ-1蛋白中对细胞功能很重要的一些关键残基，特别是半胱氨酸106，它在暴露于ROS和谷氨酸18后被修饰，谷氨酸18稳定了修饰的C106残基。 为了进一步尝试和发展我们对DJ-1的想法，我们一直在探索其功能的两个方面。 首先，我们已经开始表征DJ-1缺乏对线粒体功能的影响。 我们发现，缺乏DJ-1会导致线粒体膜电位的丧失和自噬标记物的增加，自噬是将有缺陷的线粒体从细胞中去除的过程。 第二，我们已经开发了新的突变，确定DJ-1上的功能关键位点，以防止线粒体损伤。

DJ-1 mutations are a very rare cause of recessive parkinsonism, accounting for a handful of cases worldwide. The protein involved has been shown by several laboratories to be involved in oxidative stress responses although the precise molecular function is unknown. At a cellular level, one of the effects of a loss of DJ-1 is that mitochondrial function is compromised. This may be related to oxidative stress, as mitchondria are a major source of reactive oxygen species (ROS), although this is uncertain. In prior years, we have identified some of the key residues in the DJ-1 protein that are important for cellular function, particularly cysteine 106 which becomes modified after exposure to ROS and glutamate 18, which stabilizes the modified C106 residue. To try and develop our ideas about DJ-1 further, we have been exploring two aspects of its function. First, we have started to characterize the effects of DJ-1 deficiency on mitochondrial function. We find that a lack of DJ-1 causes loss of mitochondrial membrane potential and an increase in markers of autophagy, the process by which defective mitochondria are removed from the cell. Second, we have developed novel mutations that identify functionally critical sites on DJ-1 for protection against mitochondrial damage.