Emory Parkinson's Disease Collaborative Environmental Research Center

描述(由申请人提供) 帕金森氏病(PD)涉及神经元的病理性丢失。这项研究的长期目标是了解环境和遗传神经毒剂如何相互作用，在帕金森病发病机制中发出信号并调节生存/凋亡机制。线粒体功能障碍被认为是帕金森病患者多巴胺能神经元死亡的关键机制。然而，PD相关环境毒物影响线粒体的详细分子机制！转录和活性仍不清楚。该实验室最近发表的研究结果强调了核转录因子肌细胞增强因子2(MEF2)在神经元存活中的关键作用。未发表的研究揭示了线粒体中出人意料的MEF2的存在和功能。基于此，本研究试图探讨线粒体MEF2在PD相关环境毒物在多巴胺神经元退变中的作用。具体目标是：1)。确定线粒体MEF2在多巴胺能神经元线粒体基因组转录调控中的作用；在细胞模型中研究PD相关环境毒物对线粒体MEF2的调节作用；建立毒物性帕金森病动物模型中线粒体MEF2的调控及功能。为了实现特定的目标1-3，将在多巴胺能神经细胞系SN4741和原代神经元中建立MEF2在线粒体基因转录中的作用，并将在细胞和啮齿动物模型中测试包括MPP+(MPTP的代谢物)和鱼藤酮在内的一组模型毒物，以探讨线粒体MEF2的去调节是否介导了这些毒素的毒性效应。此外，通过将线粒体MEF2的水平和活性与疾病相关联，将尝试将这些发现扩展到PD患者。这项拟议的研究将结合形态、生化、功能和遗传方法进行。这些研究将评估是否以线粒体MEF2为靶点是环境毒物诱导多巴胺神经元凋亡的基础。从这项研究中获得的新见解将展示环境毒物如何扰乱线粒体功能，为可能与散发性和家族性帕金森病相关的多巴胺神经元丢失提供分子解释，并成为潜在的治疗靶点。

DESCRIPTION (provided by applicant) Parkinson's disease (PD) involves pathological loss of neurons. The long-term objective of this research is to understand how environmental and genetic neurotoxic agents interact to signal and regulate the survival/apoptosis machinery in PD pathogenesis. Mitochondrial dysfunction has been proposed as a key mechanism that mediates demise of dopaminergic neurons in PD. However, the detailed molecular mechanisms by which PD relevant environmental toxicants affect mitochondria! transcription and activity remain unknown. Recently published findings from this lab highlight the key role of nuclear transcription factor myocyte enhancer factor 2 (MEF2) in neuronal survival. Unpublished studies have revealed unexpected presence and function of MEF2 in mitochondria. Based on this, this proposal seeks to explore the role of mitochondrial MEF2 in mediating and integrating the toxic signals of PD relevant environmental toxicants in the degeneration of dopamine neurons. The specific aims are to: 1). Determine the role of mitochondrial MEF2 in regulating transcription of mitochondrial genome in dopaminergic neurons; 2). Study the regulation of mitochondrial MEF2 by PD relevant environmental toxicants in mitochondrial dysfunction and neuronal death in cellular models; and 3). Establish the regulation and function of mitochondrial MEF2 in toxicant-induced animal models of PD. To accomplish Specific Aims 1-3 the role of MEF2 in mitochondrial gene transcription will be established in dopaminergic neuronal cell line SN4741 and primary neurons and a group of model toxicants including MPP+(metabolite of MPTP) and rotenone will be tested in cellular and rodent models to investigate whether de-regulation of mitochondrial MEF2 mediates the toxic effects of these toxins. Moreover, an attempt will be to extend these findings to PD patients by correlating the levels and activity of mitochondrial MEF2 with the disease. A combination of morphological, biochemical, functional and genetic methods will be employed in the proposed study. These studies will allow an assessment of whether or not targeting mitochondrial MEF2 underlies environmental toxicant-induced apoptosis of dopamine neurons. The novel insight gained from this study will demonstrate how environmental toxicants may disrupt mitochondrial function, providing a molecular explanation for the loss of dopamine neurons that may relevant to both sporadic and familial PD and a potential therapeutic target.