ROLE OF GLIA IN PARKINSON'S DISEASE

描述(摘自调查人员摘要) 帕金森病(PD)是美国最常见的运动障碍 各州。尽管最近在治疗方面取得了进展，但仍有迫切的需求 阻止疾病进展的新疗法，早期诊断和 识别环境和遗传危险因素的方法。帕金森是 以黑质部分多巴胺能神经元的丢失为特征 Compacta(SNPC)伴有胶质细胞增生症和氧化应激的证据， 线粒体功能障碍和铁沉积过多。虽然多巴胺 新陈代谢、环境和遗传因素被认为与 特发性帕金森病的病因，确切的原因尚不清楚。在此应用程序中， 调查人员将利用观察到的MPTP毒性是 在小鼠身上进行基因测定以表征一种新的分子信号 将这种异种生物与神经元死亡和几个 帕金森病的病理特征。 MPTP是一种异源神经毒素，可产生帕金森病的许多特征 动物模型和人类。此外，对MPTP的易感性是由物种- 依赖的，并被遗传为小鼠的显性特征。因此，小鼠 MPTP模型提供了一个独特的机会来剖析 一种典型的外源性神经毒素及其可能的遗传危险因素 与帕金森病的发病机制密切相关。 使用一种新的嵌合原代培养范例，其中分离的星形胶质细胞或 耐药或敏感品系小鼠的神经元与 不同的组合，MPTP的遗传易感性由 星形胶质细胞。这导致调查人员发现了之前 包括基因改变在内的体内对MPTP的未知反应途径 在星形胶质细胞中表达。由于这种反应涉及多巴胺代谢， 氧化应激和局部内源性神经毒素的产生，如 Iron，他们假设它既能够将MPTP链接到 SNPC多巴胺能神经元的选择性丢失及其部分原因 帕金森病的辅助病理改变。此外，作为多巴胺，而不是其他 儿茶酚胺触发了这一途径，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.