Development of therapies to retard Parkinson's disease

描述（由申请人提供）：帕金森病（PD）是一种迟发性、进行性运动疾病，以相对选择性的黑质多巴胺能降解为特征。最近的研究表明PD和线粒体NADH脱氢酶（复合物I）缺乏之间存在联系。已经证明，施用引起复合物I抑制的药剂（例如1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）或鱼藤酮）在灵长类动物或啮齿类动物中诱导PD样症状。因此，预计减轻多巴胺能细胞的复合物I的功能障碍所造成的有害影响，可能会提供一种新的补救PD。 面包酵母（Saccharomyces cerevisiae）的线粒体缺乏复合物I，但具有鱼藤酮不敏感的NADH脱氢酶（Ndi 1）。申请人已经表明，Ndi 1恢复了复合物I缺陷型哺乳动物细胞的呼吸功能，并使呼吸链对复合物I抑制剂具有抗性。此外，Ndi 1已被成功地引入多巴胺能神经大鼠PC 12和小鼠MN 9D细胞，而不损害它们的分化能力。在该提案中，申请人将采用Ndi 1酶作为治疗工具来延缓PD，并使用PD动物模型研究其潜力。 在此资助期内的研究如下： (1)啮齿类动物黑质多巴胺能神经元Ndi 1表达最适条件的优化。 (2)通过Ndi 1表达抑制啮齿动物模型中的PD疾病样症状。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a late-onset, progressive motor disease marked by relatively selective nigrostrial dopaminergic degradation. Recent studies showed a link between PD and deficiency of the mitochondrial NADH dehydrogenase (complex I). It has been demonstrated that administration of agents that cause complex I inhibition (such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone) induces PD-like symptoms in primates or rodents. It is, therefore, anticipated that relieving dopaminergic cells of harmful effects caused by the dysfunction of complex I may provide a novel remedy for PD. Mitochondria of Baker's yeast, Saccharomyces cerevisiae, lack complex I but instead has the rotenone-insensitive NADH dehydrogenase (Ndi1). The applicants have shown that Ndi1 restores respiratory function to complex I-deficient mammalian cells and renders the respiratory chain resistant to complex I inhibitors. In addition, Ndi1 has been successfully introduced into dopaminergic nerve rat PC12 and mouse MN9D cells without impairing their capability of differentiation. In this proposal, the applicants will employ the Ndi1 enzyme as a therapeutic tool to retard PD and investigate its potential using animal models for PD. The studies during this grant term are as follows: (1) Refinement of the optimum conditions of the Ndi1 expression in nigral dopaminergic neurons of rodents. (2) Suppression of PD's disease like symptoms in rodent models by the Ndi1 expression.