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.

摘要 帕金森氏病(PD)表现出的复杂而漫长的病程首先始于非运动性 障碍，然后慢慢发展为轻到中度的运动障碍，最终造成严重的运动 和认知缺陷。尽管疾病不同阶段的病理生理机制 线粒体功能障碍(MD)和神经氧化应激(OS)都尚未确定 被认为是帕金森病患者进行性神经退变过程中的关键病理相关因素。边学边学 调节黑质纹状体多巴胺能系统对MD易感性的氧化信号机制 和氧化损伤时，我们意外地发现蛋白激酶D1(PKD1)在黑质中高表达。 在氧化损伤的早期阶段，该激酶被迅速激活以保护 DAR能神经元抵抗氧化损伤。我们的机制研究表明，PKD 1被迅速激活 易位到线粒体和DAR能神经元的核。我们的初步研究表明 激活的PKD1可能增强关键的神经适应性氧化机制的转录，包括 增强了Pgc1-α、TFAM和BDNF3个信号通路。因此，本研究的目的是阐明 线粒体/核事件调控PKD1介导的代偿性保护反应 帕金森病的动物模型。我们建议的最重要的假设是，促进生存的蛋白激酶1迅速 在氧化损伤的初始阶段在黑质DAR能神经元中被激活，并迅速转移到 线粒体和细胞核启动细胞生存信号通路。它的核转位启动了关键的亲核- 生存转录机制负责Pgc1-α、TFAM和BDNf上调，导致增强 多巴胺能神经元中线粒体的生物发生和神经营养支持。蛋白激酶1的线粒体易位 通过调节线粒体质量控制(MQC)改善线粒体功能。因此，pkd1用作密钥 黑质DAR能神经元的“代偿性适应开关”。为了测试这一点，我们将系统地追求以下几点 具体目标：(I)表征PKD1的激活和核/线粒体转位及其功能 细胞培养和帕金森病动物模型的相关性；(Ii)表征下游促生存信号 在DAR能神经元中由PKD1线粒体/核转位激活的通路；以及(Iii)验证PKD1是否为 帕金森病的治疗靶点，并检测一种新的PKD1激活剂的翻译潜力。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。我们的多方面方法来利用促进DAR能的PKD1自适应信号机制 神经元存活将使我们能够设计出一种新的翻译策略，能够在过程的早期进行干预 帕金森病患者的疾病进展情况。