Compensatory Mitochondrial Protective Mechanisms Against Oxidative Stress in PD

PD 中氧化应激的补偿性线粒体保护机制

• 批准号: 10453241
• 负责人: ARTHI KANTHASAMY
• 金额: $ 43.6万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453241
• 关键词: Address; Affect; American; Animal Model; Biogenesis; Biological Models; Brain-Derived Neurotrophic Factor; CREB1 gene; Cell Culture Techniques; Cell Nucleus; Cell Survival; Cell model; Cells; Chemicals; Cognitive deficits; Complex; Disease; Disease Progression; Disease model; Exhibits; Genetic Transcription; Goals; Histologic; Histone Deacetylase; Human; Inflammatory Response; Mediating; Mitochondria; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Nuclear; Nuclear Accidents; Nuclear Protein; Nuclear Translocation; Outcomes Research; Oxidative Stress; Parkinson Disease; Pathologic; Pathway interactions; Peptides; Phosphotransferases; Predisposition; Process; Protein Kinase; Protein translocation; Protein-Serine-Threonine Kinases; Quality Control; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stress; System; Testing; Time; Transcriptional Regulation; Up-Regulation; conditional knockout; dopaminergic neuron; effective therapy; factor A; improved; innovation; mitochondrial dysfunction; mitopark mouse; motor deficit; mouse model; mtTF1 transcription factor; neurochemistry; neuroinflammation; neuronal survival; nigrostriatal system; novel; oxidative damage; preclinical efficacy; prevent; programs; protein activation; relating to nervous system; response; stem; therapeutic target; transcription factor; translational approach; translational potential; treatment strategy

Abstract The complex and prolonged disease course exhibited by Parkinson’s disease (PD) first starts with non-motor disturbances and then slowly progresses to mild-to-moderate motor deficits, ultimately inflicting severe motor and cognitive deficits. Although pathophysiological mechanisms underlying various stages of the disease have yet to be characterized, both mitochondrial dysfunction (MD) and neural oxidative stress (OS) have been identified as key pathological correlates in the progressive neurodegenerative process in PD. While studying key oxidative signaling mechanisms that regulate susceptibility of the nigrostriatal dopamin(DA)ergic system to MD and oxidative damage, we unexpectedly discovered that protein kinase D1 (PKD1) is highly expressed in nigral DAergic neurons and that the kinase is rapidly activated during the early stages of oxidative insult to protect DAergic neurons against oxidative damage. Our mechanistic studies revealed that activated PKD1 rapidly translocates to both mitochondria and the nucleus of DAergic neurons. Our preliminary studies show that activated PKD1 likely enhances the transcription of key neuro-adaptive oxidative mechanisms involving enhanced PGC1-α, TFAM and BDNF signaling pathways. Thus, the goal of this study is to elucidate mitochondrial/nuclear events governing the PKD1-mediated compensatory protective response using cell and animal models of PD. The overarching hypothesis of our proposal is that the pro-survival kinase PKD1 is rapidly activated in nigral DAergic neurons during the initial stage of an oxidative insult and quickly translocates to mitochondria and nuclei to initiate cell survival signaling pathways. Its nuclear translocation initiates key pro- survival transcriptional machinery responsible for PGC1-α, TFAM and BDNF upregulation, leading to enhanced mitochondrial biogenesis and neurotrophic support in DAergic neurons. Mitochondrial translocation of PKD1 improves mitochondrial function by regulating mitochondrial quality control (MQC). Thus, PKD1 serves as a key ‘compensatory adaptive switch’ in nigral DAergic neurons. To test this, we will systematically pursue the following specific aims: (i) characterize PKD1 activation and nuclear/mitochondrial translocation and its functional relevance in cell culture and animal models of PD; (ii) characterize the downstream pro-survival signaling pathways activated by PKD1 mitochondrial/nuclear translocation in DAergic neurons; and (iii) validate PKD1 as a therapeutic target of PD and examine the translational potential of a novel PKD1 activator. We will use multiple model systems and state-of-the-art cellular, histological and neurochemical approaches to achieve these specific aims. Our multifaceted approach to harness the PKD1 adaptive signaling mechanisms that promote DAergic neuronal survival will enable us to devise a novel translational strategy capable of intervening early in the course of disease progression in PD.

抽象的 帕金森病 (PD) 表现出复杂而漫长的病程，首先从非运动障碍开始 紊乱，然后缓慢进展为轻度至中度运动缺陷，最终造成严重的运动缺陷 和认知缺陷。尽管疾病各个阶段的病理生理机制已经 尚未确定特征，线粒体功能障碍（MD）和神经氧化应激（OS）均已被 被认为是 PD 进行性神经退行性过程的关键病理相关因素。在学习关键的同时 调节黑质纹状体多巴胺（DA）能系统对MD敏感性的氧化信号机制 和氧化损伤，我们意外地发现蛋白激酶D1（PKD1）在黑质中高表达 DAergic 神经元和激酶在氧化损伤的早期阶段迅速激活以保护 DAergic 神经元对抗氧化损伤。我们的机制研究表明，PKD1 快速激活 易位至线粒体和 DAergic 神经元的细胞核。我们的初步研究表明 激活的 PKD1 可能会增强关键神经适应性氧化机制的转录，其中包括 增强 PGC1-α、TFAM 和 BDNF 信号通路。因此，本研究的目的是阐明 线粒体/核事件利用细胞和细胞来控制 PKD1 介导的补偿性保护反应 PD动物模型。我们提议的总体假设是促生存激酶 PKD1 迅速 在氧化损伤的初始阶段，黑质DAergic神经元被激活，并迅速转移到 线粒体和细胞核启动细胞生存信号通路。它的核易位启动了关键的亲 负责 PGC1-α、TFAM 和 BDNF 上调的生存转录机制，从而增强 DAergic 神经元中的线粒体生物发生和神经营养支持。 PKD1 线粒体易位 通过调节线粒体质量控制 (MQC) 改善线粒体功能。因此，PKD1 充当密钥 黑质 DAergic 神经元中的“补偿性适应性开关”。为了测试这一点，我们将系统地进行以下操作 具体目标：(i) 表征 PKD1 激活和核/线粒体易位及其功能 与 PD 细胞培养和动物模型的相关性； (ii) 表征下游促生存信号 DAergic 神经元中 PKD1 线粒体/核易位激活的通路； (iii) 将 PKD1 验证为 PD 的治疗靶点并检查新型 PKD1 激活剂的转化潜力。我们将使用多个 模型系统和最先进的细胞、组织学和神经化学方法来实现这些特定的 目标。我们利用 PKD1 自适应信号机制的多方面方法来促进 DAergic 神经元的存活将使我们能够设计出一种能够在过程早期进行干预的新颖的翻译策略 PD 疾病进展。