Proteomic identification of nitrated proteins in Alzheimer's disease brain.
Nitration of tyrosine in biological conditions represents a pathological event that is associated with several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease (AD). Increased levels of nitrated proteins have been reported in AD brain and CSF, demonstrating the potential involvement of reactive nitrogen species (RNS) in neurodegeneration associated with this disease. Reaction of NO with O2- leads to formation of peroxynitrite ONOO-, which following protonation, generates cytotoxic species that oxidize and nitrate proteins. Several findings suggest an important role of protein nitration in modulating the activity of key enzymes in neurodegenerative disorders, although extensive studies on specific targets of protein nitration in disease are still missing. The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. We previously applied a proteomics approach to determine specific targets of protein oxidation in AD brain, by successfully coupling immunochemical detection of protein carbonyls with two-dimensional polyacrylamide gel electrophoresis and mass spectrometry analysis. In the present study, we extend our investigation of protein oxidative modification in AD brain to targets of protein nitration. The identification of six targets of protein nitration in AD brain provides evidence to the importance of oxidative stress in the progression of this dementing disease and potentially establishes a link between RNS-related protein modification and neurodegeneration.
Castegna
Alessandra
A
Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
Thongboonkerd
Visith
V
Klein
Jon B
JB
Lynn
Bert
B
Markesbery
William R
WR
Butterfield
D Allan
DA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D015153:Blotting, Western; D001923:Brain Chemistry; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000737:chemistry; D009566:Nitrates / Q000032:analysis* / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000737:chemistry; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014305:Triose-Phosphate Isomerase / Q000737:chemistry; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
D009419:Nerve Tissue Proteins; D009566:Nitrates; D011506:Proteins; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D010751:Phosphopyruvate Hydratase; D014305:Triose-Phosphate Isomerase