Journal of Neuroimmune Pharmacology

, Volume 3, Issue 2, pp 59–74

Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

  • Ashley D. Reynolds
  • Irena Kadiu
  • Sanjay K. Garg
  • Jason G. Glanzer
  • Tara Nordgren
  • Pawel Ciborowski
  • Ruma Banerjee
  • Howard E. Gendelman
Original Article

DOI: 10.1007/s11481-008-9100-z

Cite this article as:
Reynolds, A.D., Kadiu, I., Garg, S.K. et al. J Neuroimmune Pharmacol (2008) 3: 59. doi:10.1007/s11481-008-9100-z

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.

Keywords

alpha-synucleinmicrogliaParkinson’s diseaseproteomicsglutamateneuroinflammation

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ashley D. Reynolds
    • 1
    • 2
  • Irena Kadiu
    • 1
    • 2
  • Sanjay K. Garg
    • 5
    • 6
  • Jason G. Glanzer
    • 1
    • 2
    • 7
  • Tara Nordgren
    • 1
    • 2
  • Pawel Ciborowski
    • 1
    • 2
    • 3
  • Ruma Banerjee
    • 5
    • 6
  • Howard E. Gendelman
    • 1
    • 2
    • 4
  1. 1.Center for Neurovirology and Neurodegenerative DisordersUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA
  3. 3.Department of BiochemistryUniversity of Nebraska Medical CenterOmahaUSA
  4. 4.Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaUSA
  5. 5.Department of BiochemistryUniversity of Nebraska-LincolnLincolnUSA
  6. 6.Department of Biological ChemistryUniversity of Michigan Medical CenterAnn ArborUSA
  7. 7.Department of Oral Biology, College of DentistryUniversity of Nebraska Medical CenterLincolnUSA