ROLE OF GLIA IN PARKINSON'S DISEASE

描述（摘自研究者摘要） 帕金森病（PD）是美国最常见的运动障碍， States. 尽管最近在治疗方面取得了进展，但仍然迫切需要 阻止疾病进展的新疗法，用于早期诊断的手段， 识别环境和遗传风险因素的方法。 PD是 其特征在于黑质部多巴胺能神经元的损失 伴有神经胶质增生和氧化应激的证据， 线粒体功能障碍和过量铁沉积。 虽然多巴胺 代谢、环境和遗传因素都与 特发性PD的病因，确切的原因是未知的。 在本申请中， 研究人员将利用MPTP毒性是 在小鼠中进行遗传测定，以表征一种新的分子信号传导 将这种外源性物质与神经元死亡联系起来的途径， 帕金森病的病理特征 MPTP是一种异生物质神经毒素，在帕金森病中产生许多帕金森病的特征。 动物模型和人。此外，对MPTP的易感性是物种- 在小鼠中是依赖性的并且作为显性性状遗传。 因此，鼠 MPTP模型代表了一个独特的机会，剖析之间的相互作用 一种典型的外源性神经毒素和遗传风险因素， 帕金森病的发病机制 使用一种新的嵌合原代培养模式，其中分离的星形胶质细胞或 将来自小鼠的抗性或敏感品系的神经元共培养在 不同的组合，MPTP的遗传易感性是由 星形胶质细胞 这使得调查人员发现了一个以前的元素 未描述的体内MPTP反应途径，包括基因改变 在星形胶质细胞中表达。 由于这种反应涉及多巴胺代谢， 氧化应激和内源性神经毒素的局部产生，如 铁，他们假设它能够将MPTP连接到 SNpc多巴胺能神经元的选择性损失，并解释了一些 PD中的辅助病理学发现。 此外，作为多巴胺，而不是其他 儿茶酚胺触发了这条通路，它可以解释神经元 MPTP杀伤的特异性。

DESCRIPTION (Taken from the Investigator's Abstract) Parkinson's disease (PD) is the most prevalent movement disorder in the United States. Despite recent advances in treatment there remain pressing needs for novel therapies that halt disease progression, means for early diagnosis and methods to identify environmental and genetic risk factors. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by gliosis and evidence of oxidative stress, mitochondrial dysfunction and excessive iron deposition. Although dopamine metabolism, environmental and genetic factors have been implicated in the etiology of idiopathic PD, the precise cause is unknown. In this application, the investigators will exploit the observation that MPTP toxicity is genetically determined in mice to characterize a novel molecular signaling pathway that links this xenobiotic to neuronal death and several of the pathological hallmarks of PD. MPTP is a xenobiotic neurotoxin that produces many of the features of PD in animal models and man. Furthermore, susceptibility to MPTP is species- dependent and is inherited as a dominant trait in mice. Therefore, the murine MPTP model represents a unique opportunity to dissect the interaction between a prototypic exogenous neurotoxin and genetic risk factors that may contribute to the pathogenesis of PD. Using a novel chimeric primary culture paradigm where isolated astrocytes or neurons from resistant or sensitive strains of mice are co-cultured in different combinations, the genetic susceptibility to MPTP is conferred by astrocytes. This led the investigators to uncover elements of a previously undescribed response pathway to MPTP in vivo that includes alterations in gene expression in astrocytes. As this response involves dopamine metabolism, oxidative stress and the local production of endogenous neurotoxins, such as iron, they hypothesize that it is capable both of linking MPTP to the selective loss of SNpc dopaminergic neurons and accounting for some of the ancillary pathological findings in PD. Furthermore, as dopamine but not other catecholamines triggers this pathway it can account for the neuronal specificity of MPTP killing.