title: Damage to dopaminergic neurons is mediated by proliferating cell nuclear antigen through the p53 pathway under conditions of oxidative stress in a cell model of Parkinson's disease.
abstract: Oxidative stress is widely considered as a central event in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying the oxidative damage-mediated loss of dopaminergic neurons in PD are not yet fully understood. Accumulating evidence has indicated that oxidative DNA damage plays a crucial role in programmed neuronal cell death, and is considered to be at least partly responsible for the degeneration of dopaminergic neurons in PD. This process involves a number of signaling cascades and molecular proteins. Proliferating cell nuclear antigen (PCNA) is a pleiotropic protein affecting a wide range of vital cellular processes, including chromatin remodelling, DNA repair and cell cycle control, by interacting with a number of enzymes and regulatory proteins. In the present study, the exposure of PC12 cells to 1-methyl-4-phenylpyridinium (MPP+) led to the loss of cell viability and decreased the expression levels of PCNA in a dose- and time-dependent manner, indicating that this protein may be involved in the neurotoxic actions of MPP+ in dopaminergic neuronal cells. In addition, a significant upregulation in p53 expression was also observed in this cellular model of PD. p53 is an upstream inducer of PCNA and it has been recognized as a key contributor responsible for dopaminergic neuronal cell death in mouse models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. This indicates that MPP+-induced oxidative damage is mediated by the downregulation of PCNA through the p53 pathway in a cellular model of PD. Thus, our results may provide some novel insight into the molecular mechanisms responsible for the development of PD and provide new possible therapeutic targets for the treatment of PD.
authors.affiliation: Neuroscience Research Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Li
authors.affiliation: Department of Neurology, The Third Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Guang-Ren
authors.initials: GR
authors.lastname: Li
authors.affiliation: Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Bei-Lin
authors.initials: BL
authors.lastname: Zhang
authors.affiliation: Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Feng
authors.affiliation: Neuroscience Research Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage; D000818:Animals; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D015655:1-Methyl-4-phenylpyridinium