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      Cell Cycle Regulation of DNA Polymerase Beta in Rotenone-Based Parkinson's Disease Models

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          Abstract

          In Parkinson's disease (PD), neuronal cells undergo mitotic catastrophe and endoreduplication prior to cell death; however, the regulatory mechanisms remain to be defined. In this study, we investigated cell cycle regulation of DNA polymerase β (poly β) in rotenone-based dopaminergic cellular and animal models. Incubation with a low concentration (0.25 µM) of rotenone for 1.5 to 7 days resulted in a flattened cell body and decreased DNA replication during S phase, whereas a high concentration (2 µM) of rotenone exposure resulted in enlarged, multi-nucleated cells and converted the mitotic cycle into endoreduplication. Consistently, DNA poly β, which is mainly involved in DNA repair synthesis, was upregulated to a high level following exposure to 2 µM rotenone. The abrogation of DNA poly β by siRNA transfection or dideoxycytidine (DDC) treatment attenuated the rotenone-induced endoreduplication. The cell cycle was reactivated in cyclin D-expressing dopaminergic neurons from the substantia nigra (SN) of rats following stereotactic (ST) infusion of rotenone. Increased DNA poly β expression was observed in the substantia nigra pars compacta (SNc) and the substantia nigra pars reticulate (SNr) of rotenone-treated rats. Collectively, in the in vitro model of rotenone-induced mitotic catastrophe, the overexpression of DNA poly β promotes endoreduplication; in the in vivo model, the upregulation of DNA poly β and cell cycle reentry were also observed in the adult rat substantia nigra. Therefore, the cell cycle regulation of DNA poly β may be involved in the pathological processes of PD, which results in the induction of endoreduplication.

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          Most cited references 14

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          Endoreplication: polyploidy with purpose.

          A great many cell types are necessary for the myriad capabilities of complex, multicellular organisms. One interesting aspect of this diversity of cell type is that many cells in diploid organisms are polyploid. This is called endopolyploidy and arises from cell cycles that are often characterized as "variant," but in fact are widespread throughout nature. Endopolyploidy is essential for normal development and physiology in many different organisms. Here we review how both plants and animals use variations of the cell cycle, termed collectively as endoreplication, resulting in polyploid cells that support specific aspects of development. In addition, we discuss briefly how endoreplication occurs in response to certain physiological stresses, and how it may contribute to the development of cancer. Finally, we describe the molecular mechanisms that support the onset and progression of endoreplication.
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            Endoreplication and polyploidy: insights into development and disease.

            Polyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer.
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              Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation.

              Previous studies demonstrated that chronic systemic exposure to the pesticide and mitochondrial toxin rotenone through jugular vein cannulation reproduced many features of Parkinson's disease (PD) in rats, including nigrostriatal dopaminergic degeneration and formation of alpha-synuclein-positive cytoplasmic inclusions in nigral neurons (R. Betarbet et al., 2000, Nat. Neurosci. 3, 1301-1306). Although novel and conceptually important, the rotenone model of PD suffered from being extremely labor-intensive. The current paper demonstrates that these same features of PD can be reproduced by chronic, systemic exposure to rotenone following implantation of subcutaneous osmotic pumps. Chronic subcutaneous exposure to low doses of rotenone (2.0-3.0 mg/kg/day) caused highly selective nigrostriatal dopaminergic lesions. Striatal neurons containing DARPP-32 (dopamine and cAMP-regulated phosphoprotein) remained intact with normal morphology, and NeuN staining revealed normal neuronal nuclear morphology. Neurons of the globus pallidus and subthalamic nucleus were spared. Subcutaneous rotenone exposure caused alpha-synuclein-positive cytoplasmic aggregates in nigral neurons. This new protocol for chronic rotenone administration is a substantial improvement in terms of simplicity and throughput.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                10 October 2014
                : 9
                : 10
                Affiliations
                [1 ]Department of Neurology, Affiliated Hospital of Binzhou Medical University, Binzhou City, Shandong Province, China
                [2 ]Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                [3 ]Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                [4 ]Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
                [5 ]Department of Surgery, Yangxin traditional Chinese medical hospital, Yangxin County, Binzhou City, Shandong Province, China
                Hospital General Dr. Manuel Gea González, Mexico
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JBC XZL JSH TW. Performed the experiments: HCW YC. Analyzed the data: ZTZ. Contributed reagents/materials/analysis tools: WSL. Wrote the paper: HCW YC. Drafting of manuscript: WSL XZL.

                Article
                PONE-D-14-14176
                10.1371/journal.pone.0109697
                4193828
                25303312

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 10
                Funding
                This work was supported by grants (No. 81071021, No. 31171211, No. 81100958 and No. 81200983) from the National Natural Science Foundation of China (to Tao Wang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Neurology
                Neurodegenerative Diseases
                Movement Disorders
                Parkinson Disease
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

                Uncategorized

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