Zhao Junjun, Yu Shuqing, Zheng Yan, Yang Hui, Zhang Jianliang
Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing, 100069, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, State Key Disciplinary of Neurosurgery Department, Beijing, 100050, China.
Mol Neurobiol. 2017 Mar;54(2):1404-1418. doi: 10.1007/s12035-016-9743-3. Epub 2016 Feb 3.
Parkinson's disease (PD) is the second most common neurodegenerative disease. The major characteristics of PD include the loss of dopaminergic neurons in the substantia nigra and Lewy body depositions. Genetic defects, environment toxicants, and aging have been recognized as risk factors for the development of PD. Currently, although the pathogenesis of PD is still obscure, overwhelming evidence demonstrates that oxidative stress plays a central role in the progress of PD. Reactive oxygen species (ROS) function mainly through chemical reactions with atomic targets that lead to covalent oxidative modifications. Through the oxidative modification of ions, amino acids, amines, and nucleic acids, ROS exert augmented effects on the structures and functions of multiple macromolecules. These oxidative modifications can affect nucleic acid stability by oxidizing RNA, increasing mitochondrial DNA (mtDNA) mutation, and launching translesion synthesis (TLS); disturb protein homeostasis by accelerating α-synuclein aggregation, parkin aggregation, and proteasome dissociation; modulate dopamine release by activating ATP-sensitive potassium channels (K) and inactivating neuronal nicotinic acetylcholine receptors (nAChRs); and influence cellular self-defenses by promoting the cytoprotective effects of DJ-1 and PTEN-induced putative kinase 1 (PINK1) while inducing Akt dysregulation. Based on the above facts, we propose that various oxidative modifications may affect nucleic acid stability, protein homeostasis, the functionality of ion channels, and cellular self-defenses and that these processes lead to protein misfolding, dopamine depletion, and further neuronal death in PD.
帕金森病（PD）是第二常见的神经退行性疾病。PD的主要特征包括黑质中多巴胺能神经元的丧失和路易小体沉积。基因缺陷、环境毒物和衰老已被认为是PD发生发展的危险因素。目前，尽管PD的发病机制仍不清楚，但大量证据表明氧化应激在PD进展中起核心作用。活性氧（ROS）主要通过与原子靶点发生化学反应发挥作用，这些反应会导致共价氧化修饰。通过对离子、氨基酸、胺和核酸的氧化修饰，ROS对多种大分子的结构和功能产生增强作用。这些氧化修饰可通过氧化RNA、增加线粒体DNA（mtDNA）突变以及启动跨损伤合成（TLS）来影响核酸稳定性；通过加速α-突触核蛋白聚集、帕金蛋白聚集和蛋白酶体解离来扰乱蛋白质稳态；通过激活ATP敏感性钾通道（K）和使神经元烟碱型乙酰胆碱受体（nAChRs）失活来调节多巴胺释放；通过促进DJ-1和PTEN诱导的假定激酶1（PINK1）的细胞保护作用同时诱导Akt失调来影响细胞自我防御。基于上述事实，我们提出各种氧化修饰可能影响核酸稳定性、蛋白质稳态、离子通道功能和细胞自我防御，并且这些过程导致PD中的蛋白质错误折叠、多巴胺耗竭和进一步的神经元死亡。
