Identification of new Parkinson's genes playing a role in mitochondrial quality control

目前，还没有可以预防或减缓PD的疾病修饰疗法。PD与其他神经退行性疾病一样，是一种既涉及遗传因素(如PINK1和Parkin基因)又涉及环境因素(如年龄、杀虫剂)的疾病。最近，帕金森病患者的DNA的多个区域被发现与没有患上这种疾病的人不同，这表明这些差异可能与增加帕金森病的发生几率有关。然而，这些dna区域包含多个基因，因此我们必须专门确定哪个基因(S)是导致疾病风险增加的原因，以便我们能够确定PD发生的原因和方式，从而使我们能够开发新的治疗方法。从以往的研究中我们知道，大量的PD基因在维持线粒体健康方面发挥着作用，因此各种基因变化可以导致线粒体功能障碍，导致细胞死亡，从而导致PD。线粒体对细胞很重要，尤其是在脑细胞(称为神经元)中，因为它们是细胞的“动力站”，产生它们发挥功能和生存所需的能量。细胞已经开发出一种复杂的机制，将这些功能失调的线粒体从细胞中移除，这样它们就不会导致细胞死亡。这个过程被称为有丝分裂。这是由_PINK1_和_Parkin_协调的，然而，这种情况只在一些PD患者中发生，因此很可能还有其他几个基因导致PD风险。HPF实验室与AR-UK UCL DDI合作，开发了确定哪些基因在有丝分裂中发挥作用的技术。与葛兰素史克合作，我们将产生IPSC多巴胺能神经元(死于帕金森病的细胞)，并利用先进的遗传筛选技术来确定这些帕金森病风险基因中哪些调控有丝分裂。专业知识的独特融合将允许一种强大的多学科方法来加速对有丝分裂在帕金森病中的作用的深入理解，推动帕金森病的新治疗方法的设计。

Currently, there are no disease-modifying treatments that can prevent or slow down PD.PD, like other neurodegenerative conditions, is a disorder involving both genetic (e.g. _PINK1_ and _Parkin_ genes) and environmental factors (e.g. age, pesticides). Recently, multiple regions of PD patient's DNA were found to be different to those not having the disease, suggesting these differences may be involved in increasing the chances of developing PD. However, these DNA regions contain multiple genes, therefore we must specifically determine which gene(s) is responsible for increased disease risk so that we can ascertain why and how PD develops, thus allowing us to develop new therapies.From previous studies we know that a significant number of PD genes play a role in the maintenance of mitochondria health, thus various genetic changes can lead to mitochondrial dysfunction, causing cell death leading to PD. Mitochondria are important to the cell, especially in brain cells (called neurons) as they are the "power stations" of the cell, producing energy that is required for them to function and survive. Cells have developed a sophisticated mechanism to remove these dysfunctional mitochondria from the cell so that they do not cause cell death. This process is termed mitophagy. This is orchestrated by _PINK1_ and _Parkin_, however, this only happens in some PD patients, therefore there is likely to be several other genes that contribute to PD risk.The HPF lab, in collaboration with the AR-UK UCL DDI, has developed techniques to identify which genes play a role in mitophagy. In collaboration with GSK, we will generate iPSC dopaminergic neurons (cells that die in PD) and utilise advanced genetic screening techniques to determine which of these PD risk genes regulate mitophagy. The unique convergence of expertise will allow a powerful multidisciplinary approach to accelerate a deep understanding of the role of mitophagy in PD driving forward the design of novel treatments for PD.