Development of therapies to retard Parkinson's disease

描述（由申请人提供） 虽然帕金森病（PD）的原因目前尚不清楚，但 帕金森病中产生多巴胺的细胞死亡的发病机制正在密切关注， 研究了这些研究的数据表明， 多巴胺产生细胞中的复合物I可能参与PD。比如说， 给予1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）， 代谢产物（1-甲基-4-苯基吡啶离子，MPP '）作为络合物I 抑制剂，导致灵长类动物和啮齿类动物的帕金森样症状。最近， 证明了鱼藤酮，其是复合物1的特异性抑制剂， 会引发类似帕金森病的症状在其他研究中，大约40%的PD 患者表现出复合物I活性的部分缺乏。综合体I容量 据报道，产生多巴胺的细胞的数量大大低于 肝脏和肌肉因此，可以想象， 黑质中的复合物I可诱发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影响， 复合物I的功能障碍可能为PD提供新的治疗方法。 申请人已经表明，鱼藤酮不敏感的内部NADH 酿酒酵母线粒体脱氢酶（Ndi 1）恢复 呼吸功能的复合物I缺陷的哺乳动物细胞。的 NDII转导的细胞对鱼藤酮和MPP不敏感。提出要 研究Ndil蛋白保护免受 神经变性及其在延缓PD中的有效性。 在此补助金期间的研究如下： (1)NDII-重组腺相关病毒在啮齿动物模型中作为药物的用途 的PD。(2)MPTP对表达Ndil酶的转基因小鼠的作用 产生多巴胺的组织

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.