Mechanisms of mitochondrial genome integrity in familial and idiopathic Parkinson's disease

摘要 帕金森病（PD）是最常见的神经退行性运动障碍， 全世界的人都患有PD。到目前为止，治疗只是治标不治本;它们不能改变不可改变的事实。 疾病的进展。家族性和特发性PD最常见的原因是富含亮氨酸的 重复激酶2（LRRK 2）。然而，LRRK 2相关和特发性PD显示线粒体损伤， 我们对PD中线粒体功能障碍的分子基础的理解是有限的。在我们努力 了解驱动线粒体功能障碍的潜在机制，我们发现线粒体DNA 损伤是LRRK 2相关和特发性PD的共同表型。未修复线粒体 DNA损伤可具有主要的不利细胞效应，影响遗传和蛋白质不稳定性，损害 生物能量功能，增加活性氧，并引发细胞死亡。最近的初步研究 Sanders实验室的研究发现，阻断ATM的激酶活性（一种负责感知、信号和 促进DNA损伤的修复）挽救PD诱导的线粒体DNA损伤。我们进一步观察到， ATM被激活并启动DNA损伤反应途径。有趣的是，线粒体DNA修复 能力受损，伴随着特异性线粒体氧化DNA损伤的增加。的 父母资助的首要目标是了解功能失调的LRRK 2如何触发ATM介导的DNA 损伤反应途径，损害线粒体DNA修复能力，导致增加 线粒体DNA损伤，最终促进下游致病性PD级联。特定于此 研究补充，我们发现突变LRRK 2的作用延伸到核DNA损伤。 根据这些数据，冈萨雷斯-亨特博士将确定核DNA损伤的分子身份， LRRK 2和特发性PD之间的共同点。她将学习新的技术专长和方法， 有影响力的研究，并获得竞争性K赠款的关键初步数据，以启动一个独立的 科学生涯。总的来说，这个项目将直接补充父母补助金和正在进行的实验， 实验室了解LRRK 2功能障碍驱动的共享途径，以便为PD提供新的见解 病理生理学，并因此导致新的疗法。

Abstract Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and over ten million people worldwide are living with PD. To date, treatments are only symptomatic; they do not alter the inexorable progression of the disease. The most common cause of familial and idiopathic PD are mutations in leucine-rich repeat kinase 2 (LRRK2). LRRK2-associated and idiopathic PD demonstrate mitochondrial impairment, however our understanding of the molecular underpinnings of mitochondrial dysfunction in PD is limited. In our efforts to understand the underlying mechanisms driving mitochondrial dysfunction, we found that mitochondrial DNA damage is a shared phenotype amongst both LRRK2-associated and idiopathic PD. Unrepaired mitochondrial DNA damage can have major adverse cellular effects, impacting genetic and protein instability, compromising bioenergetic function, increasing reactive oxygen species, and triggering cell death. Recent preliminary studies by the Sanders lab has found that blocking kinase activity of ATM (a kinase that functions to sense, signal and promote repair of DNA damage) rescues PD-induced mitochondrial DNA damage. We further observed that ATM is activated and initiates the DNA damage response pathway. Interestingly, mitochondrial DNA repair capacity is impaired with a concomitant increase in specific mitochondrial oxidative DNA lesions. The overarching goal of the parental grant to understand how dysfunctional LRRK2 triggers the ATM-mediated DNA damage response pathway, which impairs mitochondrial DNA repair capacity, leading to an increase in mitochondrial DNA damage, ultimately promoting downstream pathogenic PD cascades. Specific to this research supplement, we have discovered that the role of mutant LRRK2 extends to nuclear DNA damage. Based on this data, Dr. Gonzalez-Hunt will determine the molecular identity of the nuclear DNA lesions that are in common between LRRK2 and idiopathic PD. She will learn new technical expertise and methodology, publish impactful research and obtain the key preliminary data for competitive K grants to launch an independent scientific career. Overall this project will directly complement the parental grant and ongoing experiments in the lab to understand shared pathways driven by LRRK2 dysfunction, in order to provide new insights into PD pathophysiology and consequently lead to new therapies.