Nitrated alpha-synuclein-activated microglial profiling for Parkinson's disease.

Abstract

Microglial neuroinflammatory processes play a primary role in dopaminergic neurodegeneration for Parkinson's disease (PD). This can occur, in part, by modulation of glial function following activation by soluble or insoluble modified alpha-synuclein (alpha-syn), a chief component of Lewy bodies that is released from affected dopaminergic neurons. alpha-Syn is nitrated during oxidative stress responses and in its aggregated form, induces inflammatory microglial functions. Elucidation of these microglial function changes in PD could lead to new insights into disease mechanisms. To this end, PD-associated inflammation was modeled by stimulation of microglia with aggregated and nitrated alpha-syn. These activated microglia were ameboid in morphology and elicited dopaminergic neurotoxicity. A profile of nitrated, aggregated alpha-syn-stimulated microglia was generated using combinations of genomic (microarrays) and proteomic (liquid chromatography-tandem mass spectrometry, differential gel electrophoresis, and protein array) assays. Genomic studies revealed a substantive role for nuclear factor-kappa B transcriptional activation. Qualitative changes in the microglial proteome showed robust increases in inflammatory, redox, enzyme, and cytoskeletal proteins supporting the genomic tests. Autopsy brain tissue acquired from substantia nigra and basal ganglia of PD patients demonstrated that parallel nuclear factor-kappa B-related inflammatory processes were, in part, active during human disease. Taken together, the transcriptome and proteome of nitrated alpha-syn activated microglia, shown herein, provide new potential insights into disease mechanisms.

• Authors: Ashley D Reynolds, Jason G Glanzer, Irena Kadiu, Mary Ricardo-Dukelow, Anathbandhu Chaudhuri, Pawel Ciborowski, Ronald Cerny, Benjamin Gelman, Mark P Thomas, R Lee Mosley, Howard E Gendelman
• Journal: Journal of neurochemistry (J Neurochem) Vol. 104 Issue 6 Pg. 1504-25 (Mar 2008) ISSN: 1471-4159 [Electronic] England
• PMID: 18036154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NF-kappa B
• Recombinant Proteins
• alpha-Synuclein
• Nitrogen

Topics

• Aged
• Aged, 80 and over
• Animals
• Cell Nucleus (metabolism)
• Cells, Cultured
• Female
• Gene Expression (physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (immunology, metabolism, pathology)
• Middle Aged
• NF-kappa B (genetics, metabolism)
• Neostriatum (metabolism, pathology)
• Neuritis (immunology, metabolism, pathology)
• Nitrogen (metabolism)
• Oxidative Stress (physiology)
• Parkinson Disease (immunology, metabolism, pathology)
• Phenotype
• Proteomics
• Recombinant Proteins (isolation & purification, metabolism)
• Substantia Nigra (metabolism, pathology)
• Transcription, Genetic (physiology)
• alpha-Synuclein (isolation & purification, metabolism)