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

目前，没有可以预防或减缓PD的疾病修饰治疗。PD与其他神经退行性疾病一样，是一种涉及遗传（例如_PINK1_和_Parkin_基因）和环境因素（例如年龄，农药）的疾病。最近，发现PD患者DNA的多个区域与未患有该疾病的患者不同，这表明这些差异可能与增加发展PD的机会有关。然而，这些DNA区域包含多个基因，因此我们必须明确确定哪些基因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。从以前的研究中我们知道，大量的PD基因在维持线粒体健康方面发挥作用，因此各种遗传变化可能导致线粒体功能障碍，导致细胞死亡导致PD。线粒体对细胞很重要，特别是在脑细胞（称为神经元）中，因为它们是细胞的“发电站”，产生它们发挥功能和生存所需的能量。细胞已经发展出一种复杂的机制来从细胞中去除这些功能失调的线粒体，这样它们就不会导致细胞死亡。这个过程被称为线粒体自噬。这是由_PINK1_和_Parkin_精心策划的，然而，这只发生在一些PD患者中，因此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，开发了识别哪些基因在线粒体自噬中起作用的技术。与GSK合作，我们将产生iPSC多巴胺能神经元（在PD中死亡的细胞），并利用先进的遗传筛选技术来确定哪些PD风险基因调节线粒体自噬。独特的专业知识融合将允许一个强大的多学科方法，以加速对线粒体自噬在PD中的作用的深入理解，推动PD新型治疗方法的设计。

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.