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.

该应用的总体目的是研究α-核蛋白（αSyn）诱导的机制路易体疾病（LBD）中的线粒体功能障碍。尽管它主要在细胞质，αSYN位于验尸后大脑中的线粒体。在线粒体内，αsyn 积累会损害复合物I和IV功能，降低膜电位，增加的水平活性氧，并增加与细胞色素c释放相关的凋亡线粒体。这些数据一起表明线粒体αSyn表达和/或有毒骨料干扰线粒体功能的异常积累。维护线粒体健康对于预防大脑神经元细胞死亡至关重要。 Sirtuin 3（Sirt3）是 NAD+依赖性蛋白脱乙酰基酶仅位于线粒体调节的线粒体线粒体过程，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以高水平表达生存因素，在兴奋性毒性条件下保护神经元中起着至关重要的作用在神经退行性模型中营救神经元损失。实验证据表明SIRT3- 诱导的针对氧化应激的神经保护因线粒体的增强而部分介导生物发生和完整性。当我们考虑基于Sirtuin的衰老疾病的药物疗法时，这是重要的是要确定调节SIRT3是否可以预防线粒体的神经变性功能障碍已被证明发挥了作用。该建议将调查线粒体如何 SIRT3在3个协调的目标中有助于αSyn诱导的线粒体功能障碍。在目标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以及使用患者衍生的细胞和验尸大脑中SIRT3的作用。在AIM 2中，我们将询问SIRT3调节的乙酰基组，以鉴定与αSyn相关的新靶线粒体功能障碍，在AIM 3中，我们将验证SIRT3作为治疗的新目标使用遗传过表达和药理激活。对各种线粒体方面的拟议严格分析将剖析后果的原因，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。