Dopamine Toxicity and Mitochondrial Dysfunction

描述（由申请人提供）：本研究将重点关注多巴胺的反应性代谢物是否可能导致帕金森病等神经退行性疾病的发病机制的基本问题。多巴胺已被证明在体外和体内对细胞都有毒性。然而，与毒性相关的确切机制尚不清楚。由于线粒体在细胞死亡机制中发挥着关键作用，因此拟议的研究旨在加深我们对多巴胺反应性代谢物与线粒体功能之间相互作用的理解，以及它们增强多巴胺能神经元损伤脆弱性的能力。在目标 1 中，我们将描述暴露于多巴胺后线粒体功能丧失和细胞死亡之间的时间关系。在目标 2 中，我们将使用纹状体黑质器官型培养物来检查多巴胺能神经元是否表现出对线粒体抑制的脆弱性增加，以及多巴胺是否有助于这种效果。最后，在目标 3 中，我们将使用质谱法确定被多巴胺醌修饰和失活的关键蛋白质的身份，重点是线粒体蛋白质。这些研究的结果有可能确定新的治疗靶点，以阻止和预防帕金森病的神经退行性过程。

DESCRIPTION (provided by applicant): This study will focus on the fundamental question of whether reactive metabolites of dopamine, may be contributing to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Dopamine has been shown to be toxic to cells both in vitro and in vivo. However, the exact mechanism associated with the toxicity is not known. Because mitochondria play a critical role in mechanisms of cell death, the proposed studies are designed to increase our understanding of the interplay between reactive metabolites of dopamine and mitochondrial function, and their ability to enhance the vulnerability of dopaminergic neurons to injury. In Aim 1, we will characterize the temporal relationship between loss of mitochondrial function and cell death following exposure to dopamine. In Aim 2, using striatonigral organotypic cultures, we will examine whether dopaminergic neurons exhibit an increased vulnerability to mitochondrial inhibition and whether dopamine contributes to this effect. Finally, in Aim 3, we will determine the identity of critical proteins modified and inactivated by dopamine quinones using mass spectrometry, with a focus on mitochondrial proteins. The outcome of these studies has potential for identifying new therapeutic targets for stopping and preventing the neurodegenerative process in Parkinson's disease.