Transcriptional regulation of metabolism in neurons

项目摘要 流行病学、遗传学和生物学证据表明，线粒体功能障碍与糖尿病的发病机制有关。 帕金森病（PD）。最近的转录研究已经确定了基因簇减少， 亚临床和症状性PD患者的黑质多巴胺能神经元，大多数 其参与神经元代谢和线粒体功能。这些发现提出了一种可能性， 代谢和线粒体基因的转录调节因子的功能可能受到损害， 特发性PD和靶向基因调控关键转录途径可能是合适的 预防和/或挽救代谢缺陷和神经元细胞死亡的策略。 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所需的， 多巴胺能黑质神经元中代谢和核编码基因转录的调节。这 雌激素相关受体β蛋白（ERR β）驱动线粒体核编码基因的表达， 它可以直接与过氧化物酶体增殖物有关， 活化受体β-辅激活因子1 β（PGC-1 β），一种在PD中减少的转录辅激活因子， 当在PD模型中过表达时具有神经保护作用。我们的初步数据表明，ERR的表达是 啮齿类动物黑质神经元，从小鼠中脑缺失ERR β会导致 ERR β-驱动的代谢基因和运动活动减少。此外，我们的数据表明，PGC-1是- 靶基因富含ERR β的结合位点，PGC-1 β和ERR β可协同驱动 线粒体基因表达重要的是，大多数线粒体基因的电子传递链 在PD中减少的是ERR靶基因。本申请中提出的实验将在这些基础上扩展 初步发现，以测试假设，ERR β是一个中央调节代谢和线粒体基因 在黑质神经元中的表达（目的1），ERR β是PGC-1 β诱导代谢和线粒体 在啮齿类动物PD模型中，ERR基因的过表达可以预防细胞功能障碍和死亡（目的2）。 (Aim 3）。这些实验有可能揭示黑质神经元维持其功能的关键途径。 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基因可以为许多减少的基因编排转录程序， 在PD中，黑质神经元中ERR β缺失可作为特发性PD的生物学相关模型。

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.