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

摘要： 黑质中脑多巴胺能神经元选择性变性及异常 -突触核蛋白在路易小体的聚集和聚集是帕金森病的显著病理特征 疾病(PD)。目前，可用的治疗是有症状的，没有可以停止或减缓的治疗。 延缓疾病的发展。基于对丙二醛神经元转录调控的广泛研究 这个实验室和其他实验室一样，孤儿核受体Nurr1(也被称为NR4A2)已经成为大师 丙二醛神经元的调节剂，是帕金森病治疗发展的一个有前途的靶点。尽管Nurr1已经 考虑到一种配体非依赖的、构成活性的转录因子，我们鉴定了两种合成的 (阿莫地喹、氯喹和格拉芬)和内源性配体(前列腺素E1(PGE1)和前列腺素A1(PGA1))，其中 直接与Nurr1的配体结合域(LBD)相互作用并激活其转录功能 机械装置。此外，我们的初步数据显示，Nurr1的表达明显受到 神经毒素暴露时间延长，-突触核蛋白过度表达。基于这些结果，我们 假设Nurr1是一种转录功能受到显著调节的“被收养的”核受体 NURR1和PD风险因子之间存在功能上的串扰。至 针对这些假设，我们建议研究以下问题。首先，我们将讨论是否 大脑中存在额外的内源性配体，并将研究其潜在的分子机制 这些新的配体如何通过识别和描绘其辅助调节因子来调节Nurr1‘S的转录功能 它们的结构-活性关系。其次，我们将调查Nurr1和Nurr1之间是否存在串扰 PD的危险因素，如-突触核蛋白以及Nurr1‘S配体如何调节这种串扰。第三，使用活体模型 我们将系统地研究Nurr1‘S最优的合成和/或内源性配体是否可以 为最终应用于帕金森病的新疗法提供基于机制的神经保护。如果成功， 这些研究将促进我们对Nurr1‘S的功能及其配体在健康和疾病中的调节的理解。 并解决Nurr1是否可以成为帕金森病的“可用药”靶点的问题。

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.