Epigenomic Mechanism of Parkinson's Disease

描述（由申请人提供）：强有力的证据表明遗传因素和环境因素在PD的发病机制中都起重要作用。在家族性帕金森病中已经发现了超过13个基因位点。衰老和许多神经毒素，包括MPTP和某些杀虫剂，是已知的人类帕金森病的危险因素。然而，疾病相关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中的相互作用，仍然知之甚少。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确定了来自一系列散发性PD患者和匹配良好的对照患者脑组织中80,000-110,000个高信息性CpG位点的全球甲基化状态，我们发现PD大脑中涉及神经发生的多个基因，特别是wnt信号通路中的基因，被高甲基化。与这一观点一致的是，对经亚致死剂量MPP+处理的SH-SY5Y细胞的全基因组表达分析显示，wnt通路基因表达减少，细胞因子基因表达增加。这些发现表明，特定的功能通路，如wnt通路，在PD的发病和进展过程中是表观遗传失调的。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地通过表观遗传机制对PD的发生和发展起着重要作用。在这项研究中，我们建议确定PD患者大脑中DNA甲基化失调的功能途径。我们还将确定已知的环境毒素是否会在小鼠模型中诱导类似的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PD发病机制中的作用，作为概念证明。该研究的成功完成将为环境因素对PD发病机制的影响提供新的见解，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.