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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，αsyn 蓄积可损害复合物I和IV的功能，降低膜电位，增加细胞膜电位的水平。活性氧，并增加与细胞色素c释放相关的细胞凋亡，线粒体总之，这些数据表明线粒体αsyn表达增加和/或毒性聚集体的异常积累干扰线粒体功能。保持线粒体健康对于防止脑中神经元细胞死亡至关重要。Sirtuin 3（SIRT 3）是一种 NAD+依赖性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组织中以高水平表达，并且可以作为促凋亡因子。生存因子，在兴奋性毒性条件下保护神经元方面发挥着重要作用，在神经变性模型中挽救神经元损失。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生物起源和完整性。当我们考虑基于去乙酰化酶的药物治疗衰老疾病时，重要的是确定调节SIRT 3是否可以防止神经变性，其中线粒体功能障碍已被证明发挥作用。这项提案将研究线粒体如何 SIRT 3在3个协调的目标中促进αsyn-induced线粒体功能障碍。在目标1中，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。在目标2中，我们将询问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作为治疗线粒体功能障碍的新靶点。使用基因过表达和药理学激活对线粒体各个方面的严格分析将从后果中剖析原因，揭示αsyn，SIRT 3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。