Transcriptional regulation of metabolism in neurons

神经元代谢的转录调控

• 批准号: 10133160
• 负责人: Rita Marie Cowell
• 金额: $ 42.39万
• 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/10133160
• 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; Electron Transport; Epidemiology; Etiology; Functional disorder; Future; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; 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 Activity; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Oxidative Stress; PARK7 gene; PINK1 gene; PPAR gamma; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral; Proteins; RNA; Regulation; Respiration; Rodent; Rodent Model; Sampling; Signal Transduction; Substantia nigra structure; Symptomatic Parkinsonism; Techniques; Testing; Therapeutic Intervention; Tissues; Transcription Coactivator; Transcriptional Regulation; base; chromatin immunoprecipitation; dopaminergic neuron; estrogen-related receptor; experimental study; gene function; improved; mitochondrial DNA mutation; mitochondrial dysfunction; motor behavior; mouse model; neuron loss; neuronal metabolism; neuronal survival; neuroprotection; novel; novel strategies; overexpression; parkin gene/protein; prevent; programs; response; transcription factor

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 γ (ERRγ), 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 γ coactivator 1α (PGC-1α), a transcriptional coactivator that is reduced in PD and can be neuroprotective when overexpressed in PD models. Our preliminary data indicate that ERRγ is expressed by neurons of the substantia nigra in rodents and that deletion of ERRγ from the mouse midbrain causes a reduction in ERRγ-driven metabolic genes and motor activity. Furthermore, our data indicate that PGC-1α- target genes are enriched in binding sites for ERRγ and that PGC-1α and ERRγ can synergistically drive mitochondrial gene expression. Importantly, the majority of mitochondrial genes of the electron transport chain reduced in PD are ERRγ target genes. The experiments proposed in this application will expand upon these initial findings to test the hypotheses that ERRγ is a central regulator of metabolic and mitochondrial gene expression in nigral neurons (Aim 1), that ERRγ is required for PGC-1α to induce metabolic and mitochondrial genes (Aim 2), and that overexpression of ERRγ 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 ERRγ can orchestrate a transcriptional program for a number of genes reduced in PD, ERRγ deletion in nigral neurons could serve as a biologically relevant model of idiopathic PD.

流行病学，遗传学和生物学证据实现线粒体功能障碍 帕金森病（PD）。最近的转录研究已经确定了降低的基因簇 亚临床和有症状性PD患者的黑质的多巴胺能神经元，大多数 参与神经元的代谢和线粒体功能。这些发现增加了 代谢基因和线粒体基因的转录调节剂的功能可能会在 特发性PD和针对基因调节的关键转录途径可能是合适的 预防和/或营救代谢的策略定义和神经元细胞死亡。 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 多巴胺能神经元中代谢和核编码基因转录的调节。这 蛋白质，与雌激素相关的受体γ（ERRγ）驱动线粒体的核编码基因的表达 外周组织中的生物发生和呼吸，它可以直接与过氧化物组增殖物相关 活化受体γ共激活因子1α（PGC-1α），一种转录共激活因子，在PD中降低，可以是 当PD模型过表达时，神经保护作用。我们的初步数据表明ERRγ是由 啮齿动物中黑质的神经元，而小鼠中脑的删除ERRγ会导致a 减少ERRγ驱动的代谢基因和运动活性。此外，我们的数据表明PGC-1α- 靶基因富含ERRγ的结合位点，并且PGC-1α和ERRγ可以协同驱动 线粒体基因表达。重要的是，电子传输链的大多数线粒体基因 PD降低的是ERRγ靶基因。本应用程序中提出的实验将扩展到这些实验 测试ERRγ是代谢和线粒体基因的中心调节剂的假设的初步发现 在nigral神经元中的表达（AIM 1），PGC-1α需要诱导代谢和线粒体需要ERRγ 基因（AIM 2），并且ERRγ的过表达可以防止PD的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ni骨神经元维持的关键途径 代谢和线粒体稳态以及改善疾病线粒体功能的新颖途径。 此外，考虑到ERRγ可以为许多基因策划的转录程序降低 在PD中，ni元神经元中的ERRγ缺失可以用作特发性PD的生物学相关模型。

项目成果

Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

• DOI: 10.1016/j.neuroscience.2021.10.007
• 发表时间: 2021-12-15
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: McMeekin, L. J.;Joyce, K. L.;Jenkins, L. M.;Bohannon, B. M.;Patel, K. D.;Bohannon, A. S.;Patel, A.;Fox, S. N.;Simmons, M. S.;Day, J. J.;Kralli, A.;Crossman, D. K.;Cowell, R. M.
• 通讯作者: Cowell, R. M.

Corrigendum to "Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain" [Neuroscience 479 (2021) 70-90].

• DOI: 10.1016/j.neuroscience.2022.05.011
• 发表时间: 2022-06-15
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: McMeekin, L. J.;Joyce, K. L.;Jenkins, L. M.;Bohannon, B. M.;Patel, K. D.;Bohannon, A. S.;Patel, A.;Fox, S. N.;Simmons, M. S.;Day, J. J.;Kralli, A.;Crossman, D. K.;Cowell, R. M.
• 通讯作者: Cowell, R. M.