Transcriptional regulation of metabolism in neurons

神经元代谢的转录调控

• 批准号: 9468448
• 负责人: Rita Marie Cowell
• 金额: $ 43.9万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9468448
• 关键词: Animal Disease Models; Behavior; Behavioral; Binding Sites; Biogenesis; Bioinformatics; Biological; Biological Assay; Cell Death; Cells; Cessation of life; Critical Pathways; DNA Binding; Data; Disease; Disease model; ERR1 protein; Electron Transport; Epidemiology; Etiology; Functional disorder; Future; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Idiopathic Parkinson Disease; Impairment; Investigation; Knock-out; Laboratories; Levodopa; Maintenance; Mediating; Mediator of activation protein; Metabolic; Metabolism; Methods; Midbrain structure; Mitochondria; Modeling; Motor; Motor Activity; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Oxidative Stress; PINK1 gene; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral; Peroxisome Proliferator-Activated Receptors; Proteins; RNA; Regulation; Respiration; Rodent; Rodent Model; Sampling; Secondary Parkinson Disease; Signal Transduction; Substantia nigra structure; Techniques; Testing; Therapeutic Intervention; Tissues; Transcript; Transcription Coactivator; Transcription Initiation Site; Transcriptional Regulation; base; chromatin immunoprecipitation; dopaminergic neuron; estrogen-related receptor; experimental study; gene function; improved; mitochondrial DNA mutation; mitochondrial dysfunction; mouse model; neuron loss; neuronal metabolism; neuronal survival; neuroprotection; novel; novel strategies; overexpression; parkin gene/protein; prevent; programs; response; transcription factor

PROJECT SUMMARY Epidemiological, genetic, and biological evidence implicates mitochondrial dysfunction in the pathogenesis of Parkinson Disease (PD). Recent transcriptional studies have identified clusters of genes reduced in dopaminergic neurons of the substantia nigra of patients with subclinical and symptomatic PD, the majority of which are involved in neuronal metabolism and mitochondrial function. These findings raise the possibility that the function of transcriptional regulators of metabolic and mitochondrial genes may be compromised in idiopathic PD and that targeting key transcriptional pathways for gene regulation may be an appropriate strategy for preventing and/or rescuing metabolic deficits and neuronal cell death. Using bioinformatics and transcriptional assays, we have identified a potential transcription factor required for the regulation of metabolic and nuclear-encoded gene transcription in dopaminergic nigral neurons. This protein, estrogen-related receptor  (ERR), drives the expression of nuclear-encoded genes for mitochondrial biogenesis and respiration in peripheral tissues, and it can directly associate with peroxisome proliferator- activated receptor  coactivator 1 (PGC-1), a transcriptional coactivator that is reduced in PD and can be neuroprotective when overexpressed in PD models. Our preliminary data indicate that ERR is expressed by neurons of the substantia nigra in rodents and that deletion of ERR from the mouse midbrain causes a reduction in ERR-driven metabolic genes and motor activity. Furthermore, our data indicate that PGC-1- target genes are enriched in binding sites for ERR and that PGC-1 and ERR can synergistically drive mitochondrial gene expression. Importantly, the majority of mitochondrial genes of the electron transport chain reduced in PD are ERR target genes. The experiments proposed in this application will expand upon these initial findings to test the hypotheses that ERR is a central regulator of metabolic and mitochondrial gene expression in nigral neurons (Aim 1), that ERR is required for PGC-1 to induce metabolic and mitochondrial genes (Aim 2), and that overexpression of ERR can prevent cell dysfunction and death in rodent model of PD (Aim 3). These experiments have the potential to reveal the critical pathways by which nigral neurons maintain metabolic and mitochondrial homeostasis and a novel avenue for improving mitochondrial function in disease. Furthermore, considering that ERR can orchestrate a transcriptional program for a number of genes reduced in PD, ERR deletion in nigral neurons could serve as a biologically relevant model of idiopathic PD.

项目概要 流行病学、遗传学和生物学证据表明线粒体功能障碍与疾病的发病机制有关 帕金森病（PD）。最近的转录研究发现，基因簇在 亚临床和有症状的帕金森病患者的黑质多巴胺能神经元，大多数 参与神经元代谢和线粒体功能。这些发现提出了这样的可能性： 代谢和线粒体基因的转录调节因子的功能可能会受到损害 特发性 PD 以及针对基因调控的关键转录途径可能是一个合适的选择 预防和/或挽救代谢缺陷和神经元细胞死亡的策略。 使用生物信息学和转录测定，我们已经确定了所需的潜在转录因子 多巴胺能黑质神经元代谢和核编码基因转录的调节。这 蛋白质，雌激素相关受体  (ERR)，驱动线粒体核编码基因的表达 外周组织的生物合成和呼吸作用，可直接与过氧化物酶体增殖物相关 激活受体  共激活因子 1 (PGC-1)，一种转录共激活因子，在 PD 中减少，可通过 在 PD 模型中过度表达时具有神经保护作用。我们的初步数据表明，ERR 表示为 啮齿类动物黑质神经元的研究表明，从小鼠中脑中删除 ERR 会导致 ERR 驱动的代谢基因和运动活动减少。此外，我们的数据表明 PGC-1α- 靶基因富含 ERR 结合位点，PGC-1 和 ERR 可以协同驱动 线粒体基因表达。重要的是，电子传递链的大多数线粒体基因 PD 中减少的是 ERR 靶基因。本申请中提出的实验将扩展这些 初步结果检验了 ERR 是代谢和线粒体基因的中央调节因子的假设 在黑质神经元中表达（目标 1），ERR 是 PGC-1 诱导代谢和线粒体所必需的 基因（目标 2），并且 ERR 的过度表达可以预防 PD 啮齿动物模型中的细胞功能障碍和死亡 （目标 3）。这些实验有可能揭示黑质神经元维持的关键途径 代谢和线粒体稳态以及改善疾病中线粒体功能的新途径。 此外，考虑到 ERR 可以为许多基因减少转录程序 在PD中，黑质神经元中的ERR-缺失可以作为特发性PD的生物学相关模型。