Identification of new components in Parkinson's Disease signalling pathways

我们的知识分子事件导致帕金森氏病（PD）正在大大提高了研究的家族形式的疾病。伍德教授的实验室已经确定了一种基因（PINK1），当突变时会导致神经细胞死亡并最终导致PD。此外，第二个基因HtrA2的点突变最近也被确定为PD的易感因素。首先出现的问题之一是，这两种分子是否相互作用在一起或在同一途径或过程中产生PD？我们最近已经确定，它们不仅在相同的途径中相互作用，而且PINK1调节HtrA2的活性。然而，还需要做更多的工作来更全面地了解这些过程。本申请侧重于这一途径，并使用一系列分子生物学和细胞技术来鉴定参与这一过程的其他蛋白质。我们计划评估这些蛋白质如何相互交谈，以及这种串扰在疾病发展中的重要性。为此，我们已经开发了适当的细胞模型的核心资源，并确定了携带PINK1基因异常的人脑组织。此外，我们将有机会接触到HtrA2和PINK1基因被破坏的小鼠和果蝇。如果我们确实能发现更多导致细胞功能障碍和死亡的途径，那么这反过来又为治疗干预提供了更多选择。

Our knowledge of the molecular events leading to Parkinson‘s disease (PD) is being greatly enhanced by the study of familial forms of the disease. Professor Wood‘s laboratory has identified a gene (PINK1) which when mutated causes nerve cell death and ultimately PD. Moreover, point mutations in a second gene called HtrA2 have also recently been identified as a susceptibility factor for PD. One of the first questions which arise is; do these two molecules interact either together or in the same pathway or process to produce PD? We have very recently established that they not only interact in the same pathway but that PINK1 regulates the activity of HtrA2. However much more work needs to be done to understand these processes more fully. This application focuses on this pathway and uses a range of molecular biological and cellular techniques to identify other proteins involved in this process. We plan to assess how these proteins talk to each other and how important this crosstalk is in the development of the disease. To this end we have already developed the core resources of appropriate cell models and have identified human brain tissue carrying abnormalities in the PINK1 gene. Moreover, we will have access to mice and flies in which HtrA2 and PINK1 genes have been disrupted.If we can indeed discover more of the pathway to cell dysfunction and death, then this in turn provides more options for therapeutic intervention.