Mechanisms of Pesticides-Induced Neuronal Apoptosis

描述（由申请人提供）：帕金森病（PD）是第二种最常见的衰老相关神经退行性疾病。其特征在于脑的黑质部（SNpc）中多巴胺能神经元的选择性损失。尽管在过去的十年中进行了大量的研究，但选择性多巴胺能神经元死亡的机制尚未得到很好的定义。虽然复合物I活性的抑制是与PD相关的多巴胺能神经元死亡的主要假设之一，但该假设尚未在遗传学上得到验证。我们的合作者Richard Palmiter博士最近培育了一种缺乏功能性Ndufs4的转基因小鼠品系，Ndufs4是一种编码复合物I完全组装和功能所需亚基的基因。我们的初步数据表明，Ndufs4基因的删除废除了复杂的I活动，中脑中脑神经元培养胚胎天（E）14小鼠。然而，与野生型小鼠的神经元相比，这些培养物中的多巴胺能神经元表现出正常和健康，在培养期间存活率没有降低。在这个建议中，我们将使用条件Ndufs4敲除小鼠，以确定复合物I抑制是一个主要的机制，潜在的多巴胺能神经元变性诱导的MPTP和鱼藤酮模型的PD在体内，并阐明复合物I抑制独立的细胞死亡机制。 公共卫生相关性：帕金森氏病是第二种最常见的与衰老相关的神经退行性疾病。我们建议阐明多巴胺能神经元死亡的分子机制在体外和体内。这些机制的研究应提供关键信息多巴胺能神经元死亡的分子基础上的几种模型的帕金森氏病，并可能提供重要的新的见解有关的分子基础帕金森氏病。

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.