Development of therapies to retard Parkinson's disease

描述(申请人提供)：帕金森病(PD)是一种起病较晚的进行性运动疾病，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与线粒体NADH脱氢酶(复合体I)缺乏之间存在联系。研究表明，1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)或鱼藤酮等引起复合体I抑制的药物可在灵长类动物或啮齿类动物中引起PD样症状。因此，预计减轻复合体I功能障碍对多巴胺能细胞的有害影响可能会为帕金森病提供一种新的治疗方法。 面包酵母的线粒体缺乏复合体I，而是具有鱼藤酮不敏感的NADH脱氢酶(Ndi1)。申请者已经证明，Ndi1可以恢复缺乏复合I的哺乳动物细胞的呼吸功能，并使呼吸链对复合I抑制剂具有抵抗力。此外，Ndi1已成功地导入多巴胺能神经大鼠PC12和小鼠MN9D细胞，而不影响其分化能力。在这项提案中，申请者将使用NDI1酶作为延缓帕金森病的治疗工具，并使用帕金森病动物模型来研究其潜力。 在这项资助期内的研究如下： (1)优化啮齿动物黑质多巴胺能神经元表达NDI1的最佳条件。 (2)表达Ndi1抑制帕金森病样症状。

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.