Crosstalk Between Nurr1 and Risk Factors of Parkinson's Disease and its Regulation by Nurr1's Ligands

摘要： 中脑黑质多巴胺能神经元选择性变性及异常 路易体中β-突触核蛋白的积累和聚集是帕金森病的标志性病理特征。 疾病（PD）。目前，可用的治疗是对症的，没有治疗可以停止或减缓 减缓疾病的发展基于对mDA神经元转录调控的广泛研究， 在这个实验室和其他实验室中，孤儿核受体Nurr 1（也称为NR 4A 2）已经成为一个大师级的受体。 mDA神经元的调节剂和PD治疗开发的有前途的目标。虽然Nurr 1已经 考虑到一个配体独立的，组成型活性转录因子，我们确定了两个合成的 （阿莫地喹、氯喹和格拉非宁）和内源性配体（前列腺素E1（PGE 1）和PGA 1）， 直接与Nurr 1的配体结合结构域（LBD）相互作用，并以不同的方式激活其转录功能。 机制等此外，我们的初步数据表明，Nurr 1的表达显着受损， 长期暴露于神经毒素和β-突触核蛋白的过度表达。基于这些结果，我们 假设Nurr 1是一种“被收养”核受体，其转录功能被显著调节 通过合成和天然配体，Nurr 1和PD风险因素之间存在功能性串扰。到 为了解决这些假设，我们建议研究以下问题。首先，我们将讨论 脑内存在其他内源性配体，并将研究潜在的分子机制。 这些新配体如何通过鉴定其共调节子和描绘Nurr 1的转录功能来调节Nurr 1， 构效关系。其次，我们将调查Nurr 1和Nurr 2之间是否存在串扰。 PD风险因素，如β-突触核蛋白和Nurr 1的配体如何调节这种串扰。第三，使用体内模型 我们将系统地研究Nurr 1的最佳合成和/或内源性配体是否可以 提供了基于机制的神经保护作用，以最终作为PD的新疗法应用。如果成功， 这些研究将促进我们对Nurr 1的功能及其配体在健康中的调节的理解， 疾病，并解决Nurr 1是否可以成为PD的“药物”目标。

Abstract: Selective degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra and abnormal accumulation and aggregation of -synuclein in Lewy bodies are hallmark pathological features of Parkinson’s disease (PD). Currently, available treatments are symptomatic and there is no treatment that can halt or slow down the disease progression. Based on extensive studies on transcriptional regulation of mDA neurons from this and other laboratories, the orphan nuclear receptor Nurr1 (also known as NR4A2) has emerged as a master regulator of mDA neurons and a promising target for therapeutic development in PD. Although Nurr1 has been considered a ligand-independent, constitutively active transcription factor, we identified both synthetic (amodiaquine, chloroquine, and glafenine) and endogenous ligands (prostaglandin E1 (PGE1) and PGA1), which directly interact with the ligand binding domain (LBD) of Nurr1 and activate its transcription function with distinct mechanisms. Furthermore, our preliminary data showed that Nurr1 expression is significantly compromised by both prolonged exposure to neurotoxin and overexpression of -synuclein. Based on these results, we hypothesize that Nurr1 is an “adopted” nuclear receptor whose transcriptional function is significantly modulated by both synthetic and native ligands and that there is functional crosstalk between Nurr1 and PD risk factors. To address these hypotheses, we propose to investigate the following questions. First, we will address whether there exist additional endogenous ligands in the brain and will investigate the underlying molecular mechanisms how these novel ligands regulate Nurr1’s transcriptional function by identifying its coregulators and delineating their structure-activity relationships. Second, we will investigate whether there is crosstalk between Nurr1 and PD risk factors such as -synuclein and how Nurr1’s ligands regulate this crosstalk. Third, using in vivo models of PD, we will systematically investigate whether Nurr1’s optimal synthetic and/or endogenous ligands can provide mechanism-based neuroprotection for eventual application as novel therapeutics for PD. If successful, these studies will advance our understanding of Nurr1’s function and regulation by its ligands in health and disease, and address whether Nurr1 can be a “druggable” target for PD.