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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：
10686813
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686813
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 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 Neurodegenerative Disorders Neurons Organelles Oxidative Stress PARK2 gene PINK1 gene PPAR gamma Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients 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 behavioral phenotyping biological adaptation to stress cytochrome c excitotoxicity in vivo mitochondrial dysfunction mutation carrier neuron loss neuroprotection new therapeutic target novel overexpression pharmacologic 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.

本应用的总体目的是研究α-突触核蛋白(α-syn)诱导的机制路易体病(LBD)的线粒体功能障碍。尽管其主要本地化在胞浆中，αSYN定位于死后LBD脑中的线粒体。在线粒体内，α同步堆积可损害复合体I和IV的功能，降低膜电位，增加血浆中活性氧物种，并增加与细胞色素c释放相关的凋亡线粒体。综上所述，这些数据表明线粒体αSYN表达和/或有毒聚集体的异常积累干扰了线粒体的功能。维护线粒体的健康对于防止大脑中的神经细胞死亡至关重要。Sirtuin 3(SIRT3)是一种 NAD+依赖的蛋白脱乙酰酶仅定位于线粒体，在那里它调节线粒体过程包括蛋白质去乙酰化、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，并可作为一种促进- 存活因子，在兴奋性毒性条件下保护神经元起着至关重要的作用挽救神经退行性变模型中的神经元丢失。实验证据表明，SIRT3- 氧化应激诱导的神经保护作用部分是通过增强线粒体来实现的生物发生和完整性。当我们考虑以sirtuin为基础的药物治疗老年病时，它是重要的是要确定调节SIRT3是否可以保护线粒体所在位置的神经变性已经证明功能障碍起到了一定的作用。这项提案将研究线粒体是如何 SIRT3在αSYN诱导的线粒体功能障碍中起3个协同作用。在目标1中，我们将进行全面的线粒体功能分析，揭示αSYN的积累是如何导致利用患者来源细胞和死后脑研究线粒体损伤和SIRT3在其中的作用。在目标2中，我们将询问sirt3调控的乙酰组以确定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作为治疗的新靶点利用基因过表达和基因治疗的综合体内方法干预帕金森病药理激活。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和线粒体之间的相互作用信号通路以及氧化和蛋白质应激反应。