Mitochondrial Sirtuin 3 in Parkinson's disease

线粒体 Sirtuin 3 在帕金森病中的作用

基本信息

批准号：
10161872
负责人：
Pamela J McLean
金额：
$ 47.65万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
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/10161872
关键词：
Adenosine Monophosphate Aging Apoptosis Autopsy Biogenesis Biological Assay Brain Brain Diseases Cell Death Cells Clinical Complex Cytosol Data Deacetylation Dementia with Lewy Bodies Diagnosis Disease Dopaminergic Cell Down-Regulation Experimental Models Fibroblasts Functional disorder Genetic Genetic Transcription Goals Health Heat shock proteins Human Impairment In Vitro Individual Knockout Mice Lewy Body Disease Mediating Membrane Potentials Mitochondria Modeling Multiple System Atrophy Mutation Neonatal Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Organelles Oxidative Stress PARK2 gene PINK1 gene PPAR gamma Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Pharmacotherapy Phosphotransferases Play Point Mutation Process Proteins Proteomics Quality Control Reactive Oxygen Species Role Signal Pathway Sir2-like Deacetylases Sirtuins Therapeutic Intervention Tissues Transgenic Mice alpha synuclein base behavioral phenotyping biological adaptation to stress cytochrome c excitotoxicity in vivo mitochondrial dysfunction mutation carrier neuron loss neuroprotection new therapeutic target novel overexpression prevent response stable cell line synucleinopathy targeted treatment

项目摘要

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.

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集中在线粒体中。在死后 LBD 大脑中，αsyn 定位于细胞质中的线粒体。积累会损害复合物 I 和 IV 功能，降低膜电位，增加活性氧，并增加与细胞色素 c 释放相关的细胞凋亡这些数据共同表明线粒体 αsyn 表达和/或增加。有毒聚集物的异常积累会干扰线粒体功能的维持。线粒体健康对于预防大脑神经细胞死亡至关重要。 Sirtuin 3 (SIRT3) 是一种细胞因子。 NAD+ 依赖性蛋白脱乙酰酶专门定位于线粒体并在那里进行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。 SIRT3 在大脑和其他神经系统组织中高水平表达，并且可以充当促生存因子，在兴奋性毒性和保护神经元的条件下发挥重要作用实验证据表明 SIRT3- 可以挽救神经退行性模型中的神经损失。诱导的针对氧化应激的神经保护作用部分是通过增强线粒体介导的当我们考虑基于沉默调节蛋白的药物疗法治疗衰老疾病时，它是重要的是确定调节 SIRT3 是否可以防止线粒体损伤的神经退行性变该提案将研究线粒体如何发挥作用。 SIRT3 在 3 个协调目标中促进 αsyn 诱导的线粒体功能障碍。在目标 1 中，我们将实现这一目标。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。在目标 2 中，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 作为治疗的新靶点使用遗传过度表达和综合体内方法干预帕金森病所提出的对线粒体各个方面的严格分析将从结果中剖析原因并揭示 αsyn、SIRT3 和线粒体之间的串扰信号通路以及氧化和蛋白质应激反应。