Nitrated alpha-synuclein and microglial neuroregulatory activities.
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.
Reynolds
Ashley D
AD
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Kadiu
Irena
I
Garg
Sanjay K
SK
Glanzer
Jason G
JG
Nordgren
Tara
T
Ciborowski
Pawel
P
Banerjee
Ruma
R
Gendelman
Howard E
HE
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
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