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Nitrated alpha‐synuclein‐activated microglial profiling for Parkinson’s disease
Author(s) -
Reynolds Ashley D.,
Glanzer Jason G.,
Kadiu Irena,
RicardoDukelow Mary,
Chaudhuri Anathbandhu,
Ciborowski Pawel,
Cerny Ronald,
Gelman Benjamin,
Thomas Mark P.,
Mosley R. Lee,
Gendelman Howard E.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05087.x
Subject(s) - microglia , neurodegeneration , substantia nigra , alpha synuclein , proteome , dopaminergic , chemistry , microbiology and biotechnology , parkinson's disease , transcriptome , neuroinflammation , inflammation , biology , neuroscience , biochemistry , dopamine , gene expression , immunology , pathology , medicine , disease , gene
J. Neurochem. (2008) 104, 1504–1525. 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 (α‐syn), a chief component of Lewy bodies that is released from affected dopaminergic neurons. α‐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 α‐syn. These activated microglia were ameboid in morphology and elicited dopaminergic neurotoxicity. A profile of nitrated, aggregated α‐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 α‐syn activated microglia, shown herein, provide new potential insights into disease mechanisms.