Mechanisms of Pesticides-Induced Neuronal Apoptosis

描述(申请人提供)：帕金森氏病(PD)是第二种最常见的与衰老有关的神经退行性疾病。它的特点是大脑黑质致密部(SNPC)多巴胺能神经元的选择性丢失。尽管在过去的十年里进行了大量的研究，但选择性多巴胺能神经元死亡的机制还没有很好地确定。尽管抑制复合体I活性是帕金森病相关的多巴胺能神经元死亡的主要假说之一，但这一假说尚未得到遗传检验。我们的合作者Richard Palmiter博士最近培育了一个缺乏功能性Ndufs4的转基因小鼠品系，Ndufs4是一种编码复合体I完全组装和功能所需的亚单位的基因。我们的初步数据表明，Ndufs4基因的缺失会取消胚胎第14天小鼠培养的中脑中脑神经元中复合体I的活性。然而，这些培养的多巴胺能神经元看起来正常和健康，与野生型小鼠的神经元相比，培养期间的存活率没有下降。在这个方案中，我们将使用条件性Ndufs4基因敲除小鼠来确定复合体I抑制是否是体内MPTP和鱼藤酮模型诱导的多巴胺能神经元变性的主要机制，并阐明复合体I抑制非依赖细胞死亡的机制。 公共卫生相关性：帕金森氏症是第二种最常见的与衰老有关的神经退行性疾病。我们建议在体外和体内阐明多巴胺能神经元死亡的分子机制。这些机制研究将提供关于帕金森病几种模型中多巴胺能神经元死亡的分子基础的关键信息，并可能提供关于帕金森病分子基础的重要新见解。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common aging-related neurodegenerative disorder. It is characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. Despite intense research in the past decade, mechanisms underlying the selective dopaminergic neuron death have not been well defined. Although inhibition of complex I activity is one of the leading hypotheses for dopaminergic neuron death associated with PD, this hypothesis has not been tested genetically. Our collaborator, Dr. Richard Palmiter, recently generated a transgenic mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Our preliminary data demonstrate that deletion of the Ndufs4 gene abolishes complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice. However, dopaminergic neurons in these cultures appeared normal and healthy with no decrease in survival during culture compared to neurons from wild-type mice. In this proposal, we will use conditional Ndufs4 knock out mice to determine if complex I inhibition is a main mechanism underlying dopaminergic neuron degeneration induced by the MPTP and rotenone models of PD in vivo and to elucidate complex I inhibition-independent mechanisms of cell death. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second most common aging-related neurodegenerative disorder. We propose to elucidate molecular mechanisms underlying dopaminergic neuron death in vitro and in vivo. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in several models of Parkinson's disease, and may provide important new insights concerning the molecular basis Parkinson's disease.