Proteomic identification of nitrated proteins in Alzheimer's disease brain

• Published in: Journal of neurochemistry Vol. 85; no. 6; pp. 1394 - 1401
• Main Authors: Castegna, Alessandra, Thongboonkerd, Visith, Klein, Jon B., Lynn, Bert, Markesbery, William R., Butterfield, D. Allan
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.06.2003; Blackwell
• Subjects: 3‐nitrotyrosine; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer's disease; Biological and medical sciences; Blotting, Western; Brain Chemistry; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Male; Medical sciences; Nerve Tissue Proteins - chemistry; neurodegeneration; Neurology; Nitrates - analysis; Nitrates - metabolism; Oxidative Stress; Peroxynitrous Acid - metabolism; Phosphopyruvate Hydratase - chemistry; Proteins - chemistry; Proteins - metabolism; Proteomics; reactive nitrogen species; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Triose-Phosphate Isomerase - chemistry; Tyrosine - analogs & derivatives; Tyrosine - analysis; Human; Tyrosine; Nitration; Nervous system diseases; Peroxynitrite; Alzheimer disease; neurodegeneration; Protein; Free radical; Cerebral disorder; Neuron; Cell death; Central nervous system disease; Proteomics; 3-nitrotyrosine; reactive nitrogen species; Degenerative disease; Oxidation; Alzheimer's disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01786.x

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 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.