Mitochondrial Sirtuin 3 in Parkinson's disease

线粒体 Sirtuin 3 在帕金森病中的作用

• 批准号: 10348483
• 负责人: Pamela J McLean
• 金额: $ 7.04万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348483
• 关键词: Aging; Apoptosis; Autopsy; Biogenesis; Brain; Brain Diseases; Cells; Complex; Cytosol; Data; Deacetylation; Disease; Experimental Models; Genetic; Goals; Health; Heat shock proteins; Impairment; Lewy Body Disease; Mediating; Membrane Potentials; Mitochondria; Modeling; Mutation; Nerve Degeneration; Nervous system structure; Neurons; Organelles; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Patients; Pharmacology; Pharmacotherapy; Play; Process; Proteins; Reactive Oxygen Species; Role; Signal Pathway; Sir2-like Deacetylases; Sirtuins; Therapeutic Intervention; Tissues; alpha synuclein; base; biological adaptation to stress; cytochrome c; excitotoxicity; in vivo; mitochondrial dysfunction; neuron loss; neuroprotection; new therapeutic target; novel; overexpression; prevent; targeted treatment

ABSTRACT The overall aim of this application is to investigate mechanisms of alpha-synuclein (αsyn)-induced mitochondrial dysfunction in Lewy body diseases (LBD). Despite its predominant localization in the cytosol, αsyn localizes to mitochondria in post-mortem LBD brains. Within the mitochondria, αsyn accumulation can impair complex I and IV function, decrease membrane potential, increase levels of reactive oxygen species, and increase apoptosis associated with cytochrome c release from the mitochondria. Together these data suggest an increase in mitochondrial αsyn expression and/or abnormal accumulation of toxic aggregates interferes with mitochondrial function. Maintaining mitochondrial health is essential to prevent neuronal cell death in the brain. Sirtuin 3 (SIRT3) is a NAD+-dependent protein deacetylase exclusively localized to the mitochondria where it regulates mitochondrial processes including protein deacetylation, organelle biogenesis, and oxidative stress. SIRT3 is expressed at high levels in the brain and other nervous system tissues, and can act as a pro- survival factor, playing an essential role in protecting neurons under conditions of excitotoxicity and rescuing neuronal loss in neurodegenerative models. Experimental evidence indicates that SIRT3- induced neuroprotection against oxidative stress is partially mediated by enhancement of mitochondrial biogenesis and integrity. As we consider sirtuin-based drug therapies for diseases of ageing, it is important to determine if modulating SIRT3 can protect against neurodegeneration where mitochondrial dysfunction has been demonstrated to play a role. This proposal will investigate how mitochondrial SIRT3 contributes to αsyn-induced mitochondrial dysfunction in 3 coordinated aims. In aim 1 we will perform comprehensive mitochondrial function analyses to reveal how αsyn accumulation leads to mitochondrial damage and the role of SIRT3 therein using patient-derived cells and postmortem brain. In aim 2 we will interrogate the SIRT3 regulated acetylome to identify novel targets of αsyn-associated mitochondrial dysfunction, and in aim 3 we will validate SIRT3 as a novel target for therapeutic intervention in PD in a comprehensive in vivo approach using genetic overexpression and pharmacological activation. The proposed rigorous analysis of various mitochondrial aspects will dissect causes from consequences and reveal the cross-talk between αsyn, SIRT3, and mitochondrial signaling pathways as well as oxidative and protein stress responses.

抽象的 本申请的总体目标是研究 α-突触核蛋白 (αsyn) 诱导的机制 路易体疾病（LBD）中的线粒体功能障碍尽管主要位于细胞质中， αsyn 定位于死后 LBD 大脑中的线粒体。在线粒体内，αsyn 积累可以。 损害复合物 I 和 IV 功能，降低膜电位，增加活性氧水平， 并增加与细胞色素 c 从线粒体释放相关的细胞凋亡。 表明线粒体 αsyn 表达增加和/或有毒聚集物异常积累 干扰线粒体功能对于预防神经元细胞的健康至关重要。 Sirtuin 3 (SIRT3) 是一种 NAD+ 依赖性蛋白脱乙酰酶，专门位于大脑中。 线粒体 调节线粒体过程，包括蛋白质脱乙酰化、细胞器 SIRT3 在大脑和其他神经系统中高水平表达。 组织，并可以作为促生存因子，在保护神经元的过程中发挥重要作用 神经退行性模型中兴奋性毒性和挽救神经元损失的条件。 表明 SIRT3 诱导的针对氧化应激的神经保护作用部分是通过增强介导的 当我们考虑基于沉默调节蛋白的疾病的药物疗法时。 随着年龄的增长，重要的是确定调节 SIRT3 是否可以预防神经退行性变 该提案将研究线粒体功能障碍如何发挥作用。 线粒体 SIRT3 在 3 个协调目标中导致 αsyn 诱导的线粒体功能障碍。 我们将进行全面的线粒体功能分析，以揭示 αsyn 积累如何导致 使用患者来源的细胞和死后大脑研究线粒体损伤以及 SIRT3 在其中的作用。 目标 2 我们将询问 SIRT3 调节的乙酰组以识别 αsyn 相关的新靶点 线粒体功能障碍，在目标 3 中，我们将验证 SIRT3 作为治疗干预的新靶点 使用遗传过度表达和药理激活的综合体内方法来治疗帕金森病。 拟议的对线粒体各个方面的严格分析将剖析原因和后果 揭示 αsyn、SIRT3 和线粒体信号通路以及氧化和信号通路之间的串扰 蛋白质应激反应。