Epigenomic Mechanism of Parkinson's Disease

描述（由申请人提供）：令人信服的证据表明遗传因素和环境因素在帕金森病的发病机制中发挥着重要作用。 Over 13 genetic loci have been identified in the familial forms of PD. Aging and a number of neurotoxins, including MPTP and certain pesticides, are known risk factors of human parkinsonia.然而，与疾病相关的环境因素的潜在分子机制，特别是它们在帕金森病发病机制中与遗传因素的相互作用，仍然知之甚少。 It is thought that epigenetic changes are mediators between genetic determinants and aging or environmental toxins.在一项初步研究中，我们利用新型测序技术确定了一系列散发性帕金森病患者和匹配良好的对照患者脑组织中80,000-110,000个高度信息化的CpG位点的整体甲基化状态，我们发现参与神经发生的多个基因，特别是wnt信号通路中的基因，在帕金森病大脑中高度甲基化。与这一观点一致的是，用亚致死剂量的 MPP 处理的 SH-SY5Y 细胞的全基因组表达分析显示，wnt 途径中基因的表达减少，同时细胞因子基因的表达增加。这些发现表明，特定的功能通路（例如 wnt 通路）在 PD 的发病机制和进展过程中出现表观遗传失调。 Our preliminary results support an important role of epigenetic regulation in PD pathogenesis.基于这些令人兴奋的初步数据，我们假设环境风险因素至少部分通过表观遗传相关机制对帕金森病的发生和进展产生显着影响。 In this study, we propose to determine the functional pathways dysregulated by DNA methylation in PD patient brains. We will also determine whether known environmental toxins induce similar changes of DNA methylation in mouse models. Finally, we will select the wnt pathway as a target to determine the role of its dysregulation in the pathogenesis of PD as proof of concept.该研究的成功完成将为了解环境因素导致帕金森病发病机制提供新的见解，并确定基因或途径作为未来治疗试剂开发的潜在靶点。

DESCRIPTION (provided by applicant): Compelling evidence suggests that both genetic factors and environmental factors play important roles in the pathogenesis of PD. Over 13 genetic loci have been identified in the familial forms of PD. Aging and a number of neurotoxins, including MPTP and certain pesticides, are known risk factors of human parkinsonia. However, the underlying molecular mechanism of the disease-associated environmental factors, particularly, their interaction with genetic factors in PD pathogenesis, remains poorly understood. It is thought that epigenetic changes are mediators between genetic determinants and aging or environmental toxins. In a preliminary study, we determined the global methylation status of 80,000-110,000 highly informative CpG sites in brain tissue from a series of sporadic PD patient and well-matched control patients utilizing novel sequencing technique and we found that multiple genes involved in neurogenesis, particularly the ones in the wnt signaling pathway, were hypermethylated in PD brains. Consistent with this notion, genome-wide expression analysis of SH-SY5Y cells treated with sub-lethal dosage of MPP+ revealed reduced expression of genes in wnt pathways along with increased expression of cytokine genes. These findings demonstrate that specific functional pathways, such as the wnt pathway, are epigenetically dysregulated during the pathogenesis and progression of PD. Our preliminary results support an important role of epigenetic regulation in PD pathogenesis. Based on these exciting preliminary data, we hypothesize that environmental risk factors contribute significantly to initiation and progression of PD via, at least partially, an epigenetic- involved mechanism. In this study, we propose to determine the functional pathways dysregulated by DNA methylation in PD patient brains. We will also determine whether known environmental toxins induce similar changes of DNA methylation in mouse models. Finally, we will select the wnt pathway as a target to determine the role of its dysregulation in the pathogenesis of PD as proof of concept. Successful completion of the study will provide novel insights into the mechanisms through which environmental factors contribute to PD pathogenesis and identify genes or pathways as potential targets for future development of therapeutic reagents.