Development of therapies to retard Parkinson's disease

开发延缓帕金森病的疗法

• 批准号: 6479808
• 负责人: TAKAO YAGI
• 金额: $ 23.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479808
• 关键词: NAD(P)H dehydrogenase; Parkinson's disease; adeno associated virus group; cell death; disease /disorder prevention /control; dopamine; enzyme activity; enzyme mechanism; gene delivery system; gene therapy; genetically modified animals; laboratory mouse; laboratory rat; methylphenyltetrahydropyridine; mitochondria; neurogenetics; nonhuman therapy evaluation; plant insecticide; substantia nigra; tissue /cell preparation; transfection /expression vector

DESCRIPTION (provided by applicant) Although the cause(s) of Parkinson's disease (PD) is unknown at present, the pathogenesis of dopamine-producing cell death in PD is being intensively investigated. The data from these studies suggest that defects in mitochondrial complex I in dopamine-producing cells may be involved in PD. For example, administration of I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whose metabolite (1-methyl-4-phenylpyridinium ion, MPP') acts as a complex I inhibitor, causes Parkinsonism-like symptoms to primates and rodents. Recently, it was demonstrated that rotenone, which is a specific inhibitor for complex 1, induces Parkinsonian-like symptoms. In other studies, approximately 40% of PD patients show partial deficiency of complex I activity. Complex I capacity in dopamine-producing cells is reported to be considerably lower than that in liver and muscle. Therefore, it is conceivable that subtle dysfunction of complex I in the substantia nigra may induce PD. If so, in order to prevent the progress of PD, relieving dopaminergic cells of harmful effects caused by dysfunction of complex I may provide a novel remedy for PD. The applicants have shown that the rotenone-insensitive internal NADH dehydrogenase (Ndi 1) of Saccharomyces cerevisiae mitochondria restores respiratory function to complex I-deficient mammalian cells. The NDII-transduced cells were insensitive to rotenone and MPP'. It is proposed to investigate the potential of the Ndil protein to protect against neurodegeneration and its effectiveness in retarding PD. The studies during this grant period are as follows: (1) Use of NDII-recombinant adeno-associated virus as a remedy in rodent models of PD. (2) Effects of MPTP on transgenic mice expressing the Ndil enzyme in the dopamine-producing tissues.

描述（由申请人提供） 尽管目前帕金森氏病（PD）的原因尚不清楚，但 PD中产生多巴胺的细胞死亡的发病机理正在密集 调查。这些研究的数据表明线粒体缺陷 多巴胺产生细胞中的复合物可能参与PD。例如， I-甲基-4-苯基1,2,3,6-四氢吡啶（MPTP）的给药 代谢产物（1-甲基-4-苯基吡啶基离子，MPP'）充当复合物I 抑制剂会导致帕金森氏症状症状引起灵长类动物和啮齿动物。最近， 已经证明烤面包酮是复合物1的特异性抑制剂， 诱发帕金森氏症症状。在其他研究中，大约40％的PD 患者表现出复杂I活性的部分缺陷。复杂的我的容量 据报道，产生多巴胺的细胞大大低于 肝脏和肌肉。因此，可以想象 黑质中的复合物可能会引起Pd。如果是这样，为了防止 PD的进展，减轻多巴胺能细胞的有害作用 复杂的功能障碍I可能为PD提供了一种新颖的疗法。 申请人表明对鱼藤酮不敏感的内部nadh 酿酒酵母线粒体的脱氢酶（NDI 1）恢复 复杂的I缺陷型哺乳动物细胞的呼吸功能。这 NDII转导的细胞对鱼藤酮和MPP'不敏感。提议 研究NDIL蛋白预防的潜力 神经变性及其在延迟PD方面的有效性。 在此赠款期间的研究如下： （1）在啮齿动物模型中，使用NDII蛋白腺相关病毒作为一种疗法 PD。 （2）MPTP对表达NDIL酶的转基因小鼠的影响 产生多巴胺的组织。