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.

摘要 本申请的总体目的是研究α-突触核蛋白（αsyn）诱导的 路易体病（Lewy body diseases，LBD）尽管其主要定位在细胞质中， αsyn定位于死后LBD脑中的线粒体。在线粒体内，α-syn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， 并增加与线粒体释放细胞色素C相关的细胞凋亡。这些数据一起 提示线粒体αsyn表达增加和/或毒性聚集物异常积累 干扰线粒体功能。维持线粒体健康对于防止神经细胞 脑中的死亡Sirtuin 3（SIRT 3）是一种NAD+依赖性蛋白脱乙酰酶，仅定位于 线粒体，调节线粒体过程，包括蛋白质脱乙酰化、细胞器 生物发生和氧化应激。SIRT 3在大脑和其他神经系统中以高水平表达 组织，并可以作为一个促生存因子，发挥重要作用，保护神经元下 在神经变性模型中的兴奋性毒性和挽救神经元损失的条件。实验证据 表明SIRT 3诱导的抗氧化应激的神经保护作用部分是通过增强 线粒体的生物发生和完整性。当我们考虑基于去乙酰化酶的药物疗法用于 随着年龄的增长，重要的是要确定调节SIRT 3是否可以防止神经变性， 线粒体功能障碍已被证明起作用。本提案将研究如何 线粒体SIRT 3在3个协调的目标中促进α-syn诱导的线粒体功能障碍。在aim 1中 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 线粒体损伤和SIRT 3在其中的作用，使用患者来源的细胞和死后的大脑。在 目的2：我们将研究SIRT 3调节的乙酰组，以确定α-syn-associated 在目标3中，我们将验证SIRT 3作为治疗干预的新靶点 在PD中使用遗传过表达和药理学活化的综合体内方法。 拟议中的对线粒体各个方面的严格分析将从后果中剖析原因， 揭示了αsyn，SIRT 3和线粒体信号通路以及氧化和 蛋白质应激反应