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Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

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Abstract

Microglial neuroinflammatory responses affect the onset and progression of Parkinson’s disease (PD). We posit that such neuroinflammatory responses are, in part, mediated by microglial interactions with nitrated and aggregated α-synuclein (α-syn) released from Lewy bodies as a consequence of dopaminergic neuronal degeneration. As disease progresses, secretions from α-syn-activated microglia can engage neighboring glial cells in a cycle of autocrine and paracrine amplification of neurotoxic immune products. Such pathogenic processes affect the balance between a microglial neurotrophic and neurotoxic signature. We now report that microglia secrete both neurotoxic and neuroprotective factors after exposure to nitrated α-syn (N-α-syn). Proteomic (surface enhanced laser desorption–time of flight, 1D sodium dodecyl sulfate electrophoresis, and liquid chromatography-tandem mass spectrometry) and limited metabolomic profiling demonstrated that N-α-syn-activated microglia secrete inflammatory, regulatory, redox-active, enzymatic, and cytoskeletal proteins. Increased extracellular glutamate and cysteine and diminished intracellular glutathione and secreted exosomal proteins were also demonstrated. Increased redox-active proteins suggest regulatory microglial responses to N-α-syn. These were linked to discontinuous cystatin expression, cathepsin activity, and nuclear factor-kappa B activation. Inhibition of cathepsin B attenuated, in part, N-α-syn microglial neurotoxicity. These data support multifaceted microglia functions in PD-associated neurodegeneration.

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Acknowledgments

We thank Dr. E. Benner for providing recombinant mouse α-synuclein and Dr. S. Appel for providing the MES23.5 cell line. The authors also thank Dr. R. Lee Mosley and Robin Taylor for critical reading of the manuscript. This work was supported by the Frances and Louie Blumkin Foundation, the Community Neuroscience Pride of Nebraska Research Initiative, and the Alan Baer Charitable Trust (to H.E.G.), a University of Nebraska Medical Center Graduate Student Excellence Award and the Patterson Fellowship (to A.R.), and NIH grants 1T32 NS07488 (to A.R. and H.E.G.), and 2R37 NS36136, PO1 NS43985, PO1 MH64570, R01 MH79886 (to H.E.G.), and DK64959 (to RB).

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  1. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Ashley D. Reynolds, Irena Kadiu, Jason G. Glanzer, Tara Nordgren, Pawel Ciborowski & Howard E. Gendelman

  2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Ashley D. Reynolds, Irena Kadiu, Jason G. Glanzer, Tara Nordgren, Pawel Ciborowski & Howard E. Gendelman

  3. Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Pawel Ciborowski

  4. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Howard E. Gendelman

  5. Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA

    Sanjay K. Garg & Ruma Banerjee

  6. Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Sanjay K. Garg & Ruma Banerjee

  7. Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE, 68583, USA

    Jason G. Glanzer

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  1. Ashley D. Reynolds
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Reynolds, A.D., Kadiu, I., Garg, S.K. et al. Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities. J Neuroimmune Pharmacol 3, 59–74 (2008). https://doi.org/10.1007/s11481-008-9100-z

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