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，超过1000万 世界各地的人都患有帕金森病。到目前为止，治疗只是有症状的；它们不能改变不可抗拒的 疾病的发展。家族性和特发性帕金森病最常见的原因是富含亮氨酸的突变 重复蛋白激酶2(LRRK2)。然而，LRRK2相关和特发性帕金森病表现为线粒体损伤 我们对帕金森病患者线粒体功能障碍的分子基础的了解有限。在我们的努力中 了解导致线粒体功能障碍的潜在机制，我们发现线粒体DNA 损伤是LRRK2相关和特发性帕金森病的共同表型。未修复的线粒体 DNA损伤可能会对细胞产生重大不利影响，影响遗传和蛋白质的不稳定性，损害 生物能量功能，增加活性氧物种，并触发细胞死亡。最近的初步研究 桑德斯实验室发现，阻断ATM(一种具有感觉、信号和信号功能的激酶)的活性 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 伴随着特定线粒体氧化DNA损伤的增加，能力受到损害。这个 父母拨款的首要目标是了解功能失调的LRRK2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 线粒体DNA损伤，最终促进下游致病PD级联反应。具体到这个 研究补充，我们发现内源性突变体LRRK2与激活的ATM相互作用，并且 这种相互作用可能是由DNA损伤引起的。根据这些数据，詹妮弗·刘将确定分子 LRRK2与ATM的相互作用及功能关系。通过这项工作，她将获得新的技术 专业知识和方法，发表有影响力的研究，并获得F31奖学金的初步数据。 总体而言，这个项目将直接补充父母的资助和正在进行的实验室实验，以了解 LRRK2的S在DNA损伤反应和帕金森病病理生理中的作用 开发新的治疗方法。

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 endogenous mutant LRRK2 interacts with activated ATM, and this interaction may be induced by DNA damage. Based on this data, Jennifer Liu will determine the molecular interactions and functional relationship between LRRK2 and ATM. Through this work, she will gain new technical expertise and methodology, publish impactful research, and obtain preliminary data for an F31 fellowship. Overall, this project will directly complement the parental grant and ongoing experiments in the lab to understand LRRK2‘s role in the DNA damage response and PD pathophysiology, which may have implications for the development of new therapies.