Nitrated Alpha-Synuclein and Microglial Neuroregulatory Activities

• Published in: Journal of neuroimmune pharmacology Vol. 3; no. 2; pp. 59 - 74
• Main Authors: Reynolds, Ashley D., Kadiu, Irena, Garg, Sanjay K., Glanzer, Jason G., Nordgren, Tara, Ciborowski, Pawel, Banerjee, Ruma, Gendelman, Howard E.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2008; Springer Nature B.V
• Subjects: alpha-Synuclein - pharmacology; alpha-Synuclein - toxicity; Animals; Biomedical and Life Sciences; Biomedicine; Cathepsin B - antagonists & inhibitors; Cathepsin B - physiology; Cell Biology; Cells, Cultured - drug effects; Cystatins - biosynthesis; Cystatins - genetics; Cysteine - secretion; Cytoskeletal Proteins - biosynthesis; Cytoskeletal Proteins - genetics; Dopamine - physiology; Gene Expression Regulation - drug effects; Glutamic Acid - secretion; Glutathione - analysis; Immunology; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - secretion; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - secretion; Neurosciences; Neurotoxicity; NF-kappa B - metabolism; Nitrates - pharmacology; Nitrates - toxicity; Original Article; Oxidation-Reduction; Oxidative Stress; Parkinson Disease - physiopathology; Parkinson's disease; Pharmacology/Toxicology; Protein Array Analysis; Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Virology; proteomics; alpha-synuclein; neuroinflammation; microglia; Parkinson’s disease; glutamate
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-008-9100-z

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.