Faculty of Medicine, Molecular and Clinical Pharmacology, ICBM, University of Chile, Santiago, Chile.
J Neurochem. 2014 Jun;129(6):898-915. doi: 10.1111/jnc.12686. Epub 2014 Mar 18.
The molecular mechanisms causing the loss of dopaminergic neurons containing neuromelanin in the substantia nigra and responsible for motor symptoms of Parkinson's disease are still unknown. The discovery of genes associated with Parkinson's disease (such as alpha synuclein (SNCA), E3 ubiquitin protein ligase (parkin), DJ-1 (PARK7), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL-1), serine/threonine-protein kinase (PINK-1), leucine-rich repeat kinase 2 (LRRK2), cation-transporting ATPase 13A1 (ATP13A), etc.) contributed enormously to basic research towards understanding the role of these proteins in the sporadic form of the disease. However, it is generally accepted by the scientific community that mitochondria dysfunction, alpha synuclein aggregation, dysfunction of protein degradation, oxidative stress and neuroinflammation are involved in neurodegeneration. Dopamine oxidation seems to be a complex pathway in which dopamine o-quinone, aminochrome and 5,6-indolequinone are formed. However, both dopamine o-quinone and 5,6-indolequinone are so unstable that is difficult to study and separate their roles in the degenerative process occurring in Parkinson's disease. Dopamine oxidation to dopamine o-quinone, aminochrome and 5,6-indolequinone seems to play an important role in the neurodegenerative processes of Parkinson's disease as aminochrome induces: (i) mitochondria dysfunction, (ii) formation and stabilization of neurotoxic protofibrils of alpha synuclein, (iii) protein degradation dysfunction of both proteasomal and lysosomal systems and (iv) oxidative stress. The neurotoxic effects of aminochrome in dopaminergic neurons can be inhibited by: (i) preventing dopamine oxidation of the transporter that takes up dopamine into monoaminergic vesicles with low pH and dopamine oxidative deamination catalyzed by monoamino oxidase (ii) dopamine o-quinone, aminochrome and 5,6-indolequinone polymerization to neuromelanin and (iii) two-electron reduction of aminochrome catalyzed by DT-diaphorase. Furthermore, dopamine conversion to NM seems to have a dual role, protective and toxic, depending mostly on the cellular context. Dopamine oxidation to dopamine o-quinone, aminochrome and 5,6-indolequinone plays an important role in neurodegeneration in Parkinson's disease since they induce mitochondria and protein degradation dysfunction; formation of neurotoxic alpha synuclein protofibrils and oxidative stress. However, the cells have a protective system against dopamine oxidation composed by dopamine uptake mediated by Vesicular monoaminergic transporter-2 (VMAT-2), neuromelanin formation, two-electron reduction and GSH-conjugation mediated by Glutathione S-transferase M2-2 (GSTM2).
导致黑质中含神经黑色素的多巴胺能神经元丧失的分子机制是帕金森病运动症状的罪魁祸首，但目前仍不清楚。与帕金森病相关基因的发现（如α-突触核蛋白（SNCA）、E3 泛素蛋白连接酶（parkin）、DJ-1（PARK7）、泛素羧基末端水解酶同工酶 L1（UCHL-1）、丝氨酸/苏氨酸蛋白激酶（PINK-1）、富亮氨酸重复激酶 2（LRRK2）、阳离子转运 ATP 酶 13A1（ATP13A）等）极大地促进了对这些蛋白质在散发性疾病中作用的基础研究。然而，科学界普遍认为线粒体功能障碍、α-突触核蛋白聚集、蛋白降解功能障碍、氧化应激和神经炎症参与神经退行性变。多巴胺氧化似乎是一个复杂的途径，其中形成多巴胺 o-醌、氨基胆色素和 5,6-吲哚醌。然而，多巴胺 o-醌和 5,6-吲哚醌都非常不稳定，难以研究并分离它们在帕金森病退行性过程中的作用。多巴胺氧化为多巴胺 o-醌、氨基胆色素和 5,6-吲哚醌似乎在帕金森病的神经退行性过程中发挥重要作用，因为氨基胆色素诱导：（i）线粒体功能障碍，（ii）α-突触核蛋白神经毒性原纤维的形成和稳定，（iii）蛋白酶体和溶酶体系统的蛋白降解功能障碍，以及（iv）氧化应激。多巴胺能神经元中氨基胆色素的神经毒性作用可以通过以下方式得到抑制：（i）通过低 pH 值摄取多巴胺的转运体和单胺氧化酶（monoamino oxidase）催化的多巴胺氧化脱氨作用来阻止多巴胺的氧化，（ii）多巴胺 o-醌、氨基胆色素和 5,6-吲哚醌聚合形成神经黑色素，以及（iii）DT-二氢二醇脱氢酶（DT-diaphorase）催化的氨基胆色素的两电子还原。此外，多巴胺转化为 NM 似乎具有保护和毒性的双重作用，这主要取决于细胞环境。多巴胺氧化为多巴胺 o-醌、氨基胆色素和 5,6-吲哚醌在帕金森病的神经退行性变中起着重要作用，因为它们诱导线粒体和蛋白降解功能障碍；形成神经毒性α-突触核蛋白原纤维和氧化应激。然而，细胞中存在一种针对多巴胺氧化的保护系统，由囊泡单胺能转运体 2（VMAT-2）介导的多巴胺摄取、神经黑色素形成、二电子还原和谷胱甘肽 S-转移酶 M2-2（GSTM2）介导的 GSH 缀合组成。
