Neural Toxicity of Paraquat is Related to Iron Regulation in the Midbrain

描述（由申请人提供）：至少有两种类型的帕金森病（PD），家族性和散发性（sPD）。到目前为止，sPD占大多数病例，并被视为几种基因及其与环境（包括广泛使用的农药）相互作用的结果。其中一种药剂是百草枯（PQ），这是一种在发展中国家和美国广泛使用的除草剂。流行病学研究中PQ暴露与sPD相关的数据不确定，我们将证明单独PQ暴露可能不足以产生sPD。至少一个其他因素是黑质中的铁含量[Fe]。SNc中的铁被认为是sPD的另一个危险因素。在体外进行的研究表明，PQ和铁协同作用，杀死多巴胺神经元的SNc，PD的病理标志。在拟议的研究中，我们将表明PQ破坏了SNc中的铁稳态，并且该组织中的铁增加是PQ神经毒性的定义。这项研究的总体目标是确定基因和基因网络，赋予差异敏感性PQ诱导增加铁在SNC。为了解决这个问题，我们将研究PQ增加铁在40个重组自交系中的作用，这些重组自交系来自C57 BL/6和DBA/2亲本品系。第一个实验将显示百草枯在SNc中增加铁的广泛的、基于遗传的变异性。第二个实验将表明，基于PQ的多巴胺神经元的破坏与PQ相关的破坏SNc中Fe稳态的程度有关。我们接下来将通过微阵列分析来研究百草枯对黑质、中脑黑质基因表达的影响，然后通过结合基因表达的QTL分析和百草枯增加SNc中铁的QTL，我们将阐明百草枯-铁神经毒性中涉及的生化途径，以及阐明表明SNc中多巴胺神经元损伤风险增加（降低）的遗传标记

DESCRIPTION (provided by applicant): There are at least two types of Parkinson's disease (PD), familial and sporadic (sPD). By far, sPD accounts for the majority of cases and is becoming to be seen as the result of several genes and their interaction with the environment, including widely used pesticides. One such agent is paraquat (PQ), an herbicide used widely in developing countries and also in the USA. The data from epidemiological studies linking PQ exposure with sPD are inconclusive and we will show that PQ exposure alone is likely insufficient to produce sPD. At least one other factor is iron content [Fe] in the substantia nigra pars compacta (SNc). Iron in the SNc is considered to be another risk factor for sPD. Studies conducted in vitro have shown that PQ and Fe act synergistically in killing dopamine neurons in the SNc, the pathological hallmark of PD. In the proposed research, we will show that PQ disrupts iron homeostasis in the SNc and that the increased iron in this tissue is what defines PQ neurotoxicity. The overall goal of this research is to identify genes and gene networks that confer differential susceptibility to PQ-induced increased Fe in the SNc. In order to address the problem, we will study the effect of PQ- increased Fe in 40 recombinant inbred strains derived from C57BL/6 and DBA/2 parental strains. The first experiment will be to show wide, genetic-based variability in paraquat- increased Fe in the SNc. The second experiment will be to show that PQ-based destruction of dopamine neurons is related to the extent of PQ-related disruption of Fe homeostasis in the SNc. We will next investigate the effects of paraquat on gene expression by microarray analysis in the substantia nigra, pars compacta and then by combining QTL analysis for the gene expression with QTL for PQ-increased Fe in the SNc, we will elucidate the biochemical pathways involved in paraquat-iron neurotoxicity as well as elucidating genetic markers that indicate increased (decreased) risk for damage to dopamine neurons in the SNc