Mechanisms of Pesticides-Induced Neuronal Apoptosis

描述（申请人提供）：帕金森病（PD）是第二常见的与衰老相关的神经退行性疾病。它的特征是大脑黑质致密部（SNpc）多巴胺能神经元的选择性丧失。尽管在过去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活性的抑制是多巴胺能神经元死亡与PD相关的主要假设之一，但这一假设尚未得到遗传学检验。我们的合作者Richard Palmiter博士最近培育了一种缺乏功能性Ndufs4的转基因小鼠菌株，Ndufs4基因编码复合体I的完整组装和功能所需的亚基。我们的初步数据表明，Ndufs4基因的缺失会消除胚胎14天小鼠培养的中脑中脑神经元中复合体I的活性。然而，与野生型小鼠相比，这些培养物中的多巴胺能神经元在培养过程中表现正常和健康，存活率没有下降。在本研究中，我们将使用条件Ndufs4敲除小鼠来确定复合物I抑制是否是MPTP和鱼藤酮模型在体内诱导多巴胺能神经元变性的主要机制，并阐明复合物I抑制不依赖于细胞死亡的机制。

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.