Abstract

Parkinson’s disease is characterized by its distinct pathological features; loss of dopamine neurons in the substantia nigra pars compacta and accumulation of Lewy bodies and Lewy neurites containing modified α-synuclein. Beneficial effects of L-DOPA and dopamine replacement therapy indicate dopamine deficit as one of the main pathogenic factors. Dopamine and its oxidation products are proposed to induce selective vulnerability in dopamine neurons. However, Parkinson’s disease is now considered as a generalized disease with dysfunction of several neurotransmitter systems caused by multiple genetic and environmental factors. The pathogenic factors include oxidative stress, mitochondrial dysfunction, α-synuclein accumulation, programmed cell death, impaired proteolytic systems, neuroinflammation, and decline of neurotrophic factors. This paper presents interactions among dopamine, α-synuclein, monoamine oxidase, its inhibitors, and related genes in mitochondria. α-Synuclein inhibits dopamine synthesis and function. Vice versa, dopamine oxidation by monoamine oxidase produces toxic aldehydes, reactive oxygen species, and quinones, which modify α-synuclein, and promote its fibril production and accumulation in mitochondria. Excessive dopamine in experimental models modifies proteins in the mitochondrial electron transport chain and inhibits the function. α-Synuclein and familiar Parkinson’s disease-related gene products modify the expression and activity of monoamine oxidase. Type A monoamine oxidase is associated with neuroprotection by an unspecific dose of inhibitors of type B monoamine oxidase, rasagiline and selegiline. Rasagiline and selegiline prevent α-synuclein fibrillization, modulate this toxic collaboration, and exert neuroprotection in experimental studies. Complex interactions between these pathogenic factors play a decisive role in neurodegeneration in PD and should be further defined to develop new therapies for Parkinson’s disease.

中文翻译：

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多巴胺、α-突触核蛋白、单胺氧化酶和帕金森病线粒体基因之间的毒性相互作用

摘要

帕金森病具有鲜明的病理特征；黑质致密部多巴胺神经元的损失以及含有修饰的α-突触核蛋白的路易体和路易神经突的积累。左旋多巴和多巴胺替代疗法的有益作用表明多巴胺缺乏是主要致病因素之一。多巴胺及其氧化产物被认为可诱导多巴胺神经元的选择性脆弱性。然而，帕金森病现在被认为是一种由多种遗传和环境因素引起的多种神经递质系统功能障碍的全身性疾病。致病因素包括氧化应激、线粒体功能障碍、α-突触核蛋白积累、程序性细胞死亡、蛋白水解系统受损、神经炎症和神经营养因子下降。本文介绍了线粒体中多巴胺、α-突触核蛋白、单胺氧化酶、其抑制剂和相关基因之间的相互作用。α-突触核蛋白抑制多巴胺的合成和功能。反之亦然，多巴胺被单胺氧化酶氧化产生有毒的醛、活性氧和醌，它们修饰α-突触核蛋白，并促进其在线粒体中原纤维的产生和积累。实验模型中过量的多巴胺会修饰线粒体电子传递链中的蛋白质并抑制其功能。α-突触核蛋白和熟悉的帕金森病相关基因产物可改变单胺氧化酶的表达和活性。A 型单胺氧化酶与非特定剂量的 B 型单胺氧化酶抑制剂雷沙吉兰和司来吉兰的神经保护作用有关。雷沙吉兰和司来吉兰可预防 α-突触核蛋白原纤维化，调节这种毒性协作，并在实验研究中发挥神经保护作用。这些致病因素之间复杂的相互作用在帕金森病的神经变性中起着决定性作用，应进一步明确这些因素以开发帕金森病的新疗法。