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Oxidative Modification and Its Implications for the Neurodegeneration of Parkinson’s Disease

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Abstract

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 (KATP) 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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (31571202, 31271136, and 81371398), the Young Talents Cultivation Plan in Beijing Local University (CIT and TCD201504087), the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ201210025020 and 7131001), and the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (IDHT20140514).

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  1. 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

    Junjun Zhao, Yan Zheng, Hui Yang & Jianliang Zhang

  2. 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

    Shuqing Yu

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  1. Junjun Zhao
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Zhao, J., Yu, S., Zheng, Y. et al. Oxidative Modification and Its Implications for the Neurodegeneration of Parkinson’s Disease. Mol Neurobiol 54, 1404–1418 (2017). https://doi.org/10.1007/s12035-016-9743-3

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