Mitochondrial mechanisms of redox cycling agents

描述(由申请人提供)：这项提案的长期目标是确定环境因素导致神经退化的机制。环境神经毒物与帕金森病(PD)等神经退行性疾病的病因学密切相关。在环境中发现了氧化还原循环剂，如除草剂百草枯(PQ2+)，这类化合物中的几种化合物已被作为神经毒性物质进行研究，其基础是在有氧环境中产生活性氧物种(ROS)的能力，以及流行病学报告将它们的暴露与帕金森病风险增加联系起来。然而，环境氧化还原循环剂产生ROS以及由此产生的神经毒性的细胞和分子机制仍不完全清楚。据推测，线粒体在氧化还原循环剂产生ROS以及由此产生的神经毒性中起关键作用。该假说预测，氧化还原循环剂，如PQ2+，通过电子传递链的电子部分还原形成PQ+的机制增加线粒体ROS的产生。自由基通过络合物III作为氧化还原酶。该假说进一步预测，线粒体是氧化还原循环剂的目标，清除线粒体氧化剂将减轻神经毒性。为解决这一问题，提出了以下具体目标。具体目的1：确定氧化还原循环剂对线粒体产生ROS和神经毒性的作用机制。具体目标2：确定线粒体是否是体内多巴胺能细胞中氧化还原循环剂产生的氧化应激的来源和靶点。具体目标3：确定线粒体靶向治疗是否改善体内给予氧化还原循环剂所产生的线粒体氧化应激和神经毒性。这些研究可以阐明暴露于环境氧化还原循环剂可损伤多巴胺能神经元的机制，并为治疗神经毒物诱导的帕金森病提供一种合理的治疗方法。公共卫生相关性稳步增长的文献表明，环境因素本身，或与遗传因素或其他毒物相结合，可能使个人容易患上神经退行性疾病，如帕金森氏病(PD)。百草枯和敌草枯是广泛使用的典型氧化还原循环环境制剂，有可能导致帕金森综合症。这些药剂作为景观和水生除草剂的广泛使用凸显了它们的环境和职业风险的重要性。因此，阐明这类药物的分子机制和开发合理的穿透血脑屏障的治疗策略是至关重要的。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to determine the mechanisms by which environmental agents produce neurodegeneration. Environmental neurotoxicants are strongly implicated in the etiology of neurodegenerative diseases such as Parkinson's disease (PD). Redox cycling agents such as the herbicide paraquat (PQ2+) are found in the environment and several compounds in this class have come under investigation as neurotoxic agents based on the ability to produce reactive oxygen species (ROS) in an aerobic environment and epidemiological reports linking their exposure with increased risk of PD. However, the cellular and molecular mechanisms by which environmental redox cycling agents produce ROS and resultant neurotoxicity remain incompletely understood. It is hypothesized that the mitochondria play a key role in ROS production by redox cycling agents and consequent neurotoxicity. The hypothesis predicts that redox cycling agents such as PQ2+ increase mitochondrial ROS production by a mechanism involving its partial reduction by electrons of the electron transport chain to form the PQ+. radical via complex III as the redox enzyme. The hypothesis further predicts that mitochondria are a target of redox cycling agents and scavenging mitochondrial oxidants will ameliorate neurotoxicity. To address this, the following specific aims are proposed. Specific Aim 1: Determine the mitochondrial mechanism of ROS generation and neurotoxicity by redox cycling agents. Specific Aim 2: Determine if mitochondria are a source and a target of oxidative stress produced by redox cycling agents in dopaminergic cells in vivo. Specific Aim 3: Determine if mitochondrially targeted therapies ameliorate mitochondrial oxidative stress and neurotoxicity produced by in vivo administration of redox cycling agents. These studies can elucidate the mechanism by which exposure to environmental redox cycling agents can injure dopaminergic neurons and provide a rational therapy to treat neurotoxicant-induced Parkinson's disease. PUBLIC HEALTH RELEVANCE A steadily growing body of literature suggests that environmental agents alone, or in combination with genetic factors or other toxicants may predispose individuals to neurodegenerative diseases such as Parkinson's disease (PD). Paraquat and diquat are widely used prototypical redox cycling environmental agents with the potential of causing parkinsonism. The extensive use of these agents as a landscape and aquatic herbicides underscores the importance of their environmental and occupational risk. Therefore, elucidating the molecular mechanisms of such agents and development of rational therapeutic strategies that penetrate the blood brain barrier is critical.