Development of therapies to retard Parkinson's disease

描述(由申请人提供) 虽然目前帕金森氏病(PD)的病因(S)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研究中 调查过了。这些研究的数据表明线粒体中的缺陷 多巴胺产生细胞中的复合体I可能与帕金森病有关。例如, 1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的给药，其 代谢产物(1-甲基-4-苯基吡啶离子，MPP‘)作为络合物I 抑制剂，会导致灵长类动物和啮齿类动物出现帕金森样症状。最近， 研究表明，鱼藤酮是化合物1的特异性抑制物， 会引发类似帕金森症的症状。在其他研究中，大约40%的帕金森病 患者表现为复合体I活性部分缺乏。中的复杂i容量 据报道，产生多巴胺的细胞数量大大低于 肝脏和肌肉。因此，可以想象，微妙的功能障碍 黑质复合体I可诱发帕金森病。如果是这样，为了防止 帕金森病的研究进展，减轻多巴胺能细胞对帕金森病的有害影响 复合体I的功能障碍可能为帕金森病提供一种新的治疗方法。 申请人已经证明，鱼藤酮不敏感的内部NADH 酿酒酵母线粒体脱氢酶(NDI-1)的修复 对复杂的i缺陷哺乳动物细胞的呼吸功能。这个 转导NDII的细胞对鱼藤酮和MPP‘不敏感。现建议： 研究Ndil蛋白的潜在免疫保护作用 神经退行性变及其延缓帕金森病的有效性。 在此资助期间进行的研究如下： (1)用NdiI重组腺相关病毒治疗啮齿动物模型 警局的。(2)MPTP对表达Ndil酶的转基因小鼠的影响 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.