Epigenomic Mechanism of Parkinson's Disease

描述(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都起着重要的作用。在家族性帕金森病中已发现13个以上的遗传位点。衰老和一些神经毒素，包括MPTP和某些杀虫剂，是人类帕金森症的已知风险因素。然而，与疾病相关的环境因素的潜在分子机制，特别是它们与遗传因素在帕金森病发病机制中的相互作用，目前仍不清楚。表观遗传变化被认为是遗传决定因素与衰老或环境毒素之间的中介。在一项初步研究中，我们利用新的测序技术检测了一系列散发性帕金森病患者和匹配良好的对照组患者脑组织中80,000-110,000个高度信息量的CpG位点的全球甲基化状态，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，在帕金森病患者的大脑中发生了高甲基化。与这一观点一致，对亚致死剂量MPP处理的SH-SY5Y细胞的全基因组表达分析显示，WNT途径中的基因表达减少，而细胞因子基因的表达增加。这些发现表明，特定的功能通路，如WNT通路，在PD的发病和发展过程中存在表观遗传失调。我们的初步结果支持表观遗传调控在帕金森病发病机制中的重要作用。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机制对帕金森病的启动和进展起到重要作用。在这项研究中，我们建议确定帕金森病患者大脑中DNA甲基化失调的功能通路。我们还将确定已知的环境毒素是否会在小鼠模型中引起类似的DNA甲基化变化。最后，我们将选择WNT通路作为靶点，以确定其失调在帕金森病发病机制中的作用，作为概念验证。这项研究的成功完成将为环境因素在帕金森病发病机制中的作用机制提供新的见解，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.