title: Nitrated alpha-synuclein and microglial neuroregulatory activities.
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 alpha-synuclein (alpha-syn) released from Lewy bodies as a consequence of dopaminergic neuronal degeneration. As disease progresses, secretions from alpha-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 alpha-syn (N-alpha-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-alpha-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-alpha-syn. These were linked to discontinuous cystatin expression, cathepsin activity, and nuclear factor-kappa B activation. Inhibition of cathepsin B attenuated, in part, N-alpha-syn microglial neurotoxicity. These data support multifaceted microglia functions in PD-associated neurodegeneration.
authors.affiliation: Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Reynolds
authors.forename: Irena
authors.initials: I
authors.lastname: Kadiu
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Garg
authors.forename: Jason G
authors.initials: JG
authors.lastname: Glanzer
authors.forename: Tara
authors.initials: T
authors.lastname: Nordgren
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D015891:Cystatins / Q000096:biosynthesis / Q000235:genetics; D003545:Cysteine / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004298:Dopamine / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000503:physiopathology; D040081:Protein Array Analysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D051844:alpha-Synuclein / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D015891:Cystatins; D003598:Cytoskeletal Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009566:Nitrates; D051844:alpha-Synuclein; D018698:Glutamic Acid; D002401:Cathepsin B; D005978:Glutathione; D003545:Cysteine; D004298:Dopamine