Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease

Authors

  • Ashley D. Reynolds,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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    • Both these authors contributed equally to this study.

  • Jason G. Glanzer,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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    • The present address of Jason G. Glanzer is the Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA.

    • Both these authors contributed equally to this study.

  • Irena Kadiu,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Mary Ricardo-Dukelow,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
    3. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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    • The present address of Mary Ricardo-Dukelow is the Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA.

  • Anathbandhu Chaudhuri,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Pawel Ciborowski,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Ronald Cerny,

    1. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
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  • Benjamin Gelman,

    1. Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
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  • Mark P. Thomas,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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    • The present address of Mark P. Thomas is the School of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA.

  • R. Lee Mosley,

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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  • Howard E. Gendelman

    1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA
    2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
    3. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Address correspondence and reprint requests to Howard E. Gendelman, MD, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880. E-mail: hegendel@unmc.edu

Abstract

J. Neurochem. (2008) 104, 1504–1525.

Abstract

Microglial neuroinflammatory processes play a primary role in dopaminergic neurodegeneration for Parkinson’s disease (PD). This can occur, in part, by modulation of glial function following activation by soluble or insoluble modified alpha-synuclein (α-syn), a chief component of Lewy bodies that is released from affected dopaminergic neurons. α-Syn is nitrated during oxidative stress responses and in its aggregated form, induces inflammatory microglial functions. Elucidation of these microglial function changes in PD could lead to new insights into disease mechanisms. To this end, PD-associated inflammation was modeled by stimulation of microglia with aggregated and nitrated α-syn. These activated microglia were ameboid in morphology and elicited dopaminergic neurotoxicity. A profile of nitrated, aggregated α-syn-stimulated microglia was generated using combinations of genomic (microarrays) and proteomic (liquid chromatography-tandem mass spectrometry, differential gel electrophoresis, and protein array) assays. Genomic studies revealed a substantive role for nuclear factor-kappa B transcriptional activation. Qualitative changes in the microglial proteome showed robust increases in inflammatory, redox, enzyme, and cytoskeletal proteins supporting the genomic tests. Autopsy brain tissue acquired from substantia nigra and basal ganglia of PD patients demonstrated that parallel nuclear factor-kappa B-related inflammatory processes were, in part, active during human disease. Taken together, the transcriptome and proteome of nitrated α-syn activated microglia, shown herein, provide new potential insights into disease mechanisms.

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