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

Research output: Contribution to journalArticle

86 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)59-74
Number of pages16
JournalJournal of Neuroimmune Pharmacology
Volume3
Issue number2
DOIs
StatePublished - Jun 2008

Keywords

  • Alpha-synuclein
  • Glutamate
  • Microglia
  • Neuroinflammation
  • Parkinson's disease
  • Proteomics

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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