Transcriptional regulation of metabolism in neurons

流行病学、遗传学和生物学证据表明线粒体功能障碍与该病的发病有关 帕金森病(PD)。最近的转录研究发现了一组基因的减少 亚临床和症状性帕金森病患者黑质中的多巴胺能神经元 它们参与神经元新陈代谢和线粒体功能。这些发现增加了这样一种可能性 代谢和线粒体基因的转录调节功能可能在 特发性帕金森病和以关键转录通路为靶点进行基因调控可能是合适的 预防和/或挽救代谢缺陷和神经细胞死亡的策略。 利用生物信息学和转录分析，我们已经确定了一个潜在的转录因子，它需要 多巴胺能黑质神经元代谢和核编码基因转录的调控。这 雌激素相关受体γ(ERRγ)蛋白驱动线粒体核编码基因的表达 在外周组织中的生物发生和呼吸作用，并可直接与过氧化物酶体增殖物- 激活的受体γ共激活因子1α(PGC-1α)，是一种转录辅助激活因子，在帕金森病中减少，可以 在帕金森病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，ERRγ由下式表示 啮齿动物黑质神经元和小鼠中脑ERRγ缺失导致 ERRγ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ERRγ结合位点，pGC-1α和ERRγ可协同驱动 线粒体基因表达。重要的是，大多数电子传输链的线粒体基因 PD减少的是Errγ靶基因。本申请中提出的实验将在这些基础上进行扩展 检验Errγ是代谢和线粒体基因中枢调节因子假说的初步发现 在黑质神经元中的表达(目标1)，错误的γ是前列腺素C-1α诱导代谢和线粒体所必需的 目的2基因和ERRγ过表达可预防帕金森病鼠模型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通路 代谢和线粒体动态平衡以及改善疾病中线粒体功能的新途径。 此外，考虑到Errγ可以为一些减少的基因编排转录程序 在帕金森病中，黑质神经元ERRγ缺失可作为特发性帕金森病的生物学相关模型。

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.