Abbreviations used : Aβ, amyloid β-peptide ; AD, Alzheimer's disease ; ALS, amyotrophic lateral sclerosis ; EPR, electron paramagnetic resonance ; GS, glutamine synthase ; iNOS, inducible isoform of nitric oxide synthase ; MAL-6, 2,2,6,6-tetramethyl-4-maleimidopiperidine-1-oxyl ; nNOS, nitric oxide synthase synthesized in neurons ; NO, nitric oxide, NOS, nitric oxide synthase ; ONOO-, peroxynitrite ; ONOOH, peroxynitrous acid ; RNS, reactive nitrogen species ; ROS, reactive oxygen species ; S, strongly immobilized component ; W, weakly immobilized component.
Peroxynitrite-Induced Alterations in Synaptosomal Membrane Proteins
Insight into Oxidative Stress in Alzheimer's Disease
Article first published online: 18 JAN 2002
Journal of Neurochemistry
Volume 72, Issue 1, pages 310–317, January 1999
How to Cite
Koppal, T., Drake, J., Yatin, S., Jordan, B., Varadarajan, S., Bettenhausen, L. and Butterfield, D. A. (1999), Peroxynitrite-Induced Alterations in Synaptosomal Membrane Proteins. Journal of Neurochemistry, 72: 310–317. doi: 10.1046/j.1471-4159.1999.0720310.x
- Issue published online: 18 JAN 2002
- Article first published online: 18 JAN 2002
- Nitric oxide;
- Alzheimer's disease;
- Protein oxidation;
Abstract : Peroxynitrite (ONOO-) is a highly reactive, oxidizing anion with a half-life of <1 s that is formed by reaction of superoxide radical anion with nitric oxide. Several reports of ONOO- -induced oxidation of lipids, proteins, DNA, sulfhydryls, and inactivation of key enzymes have appeared. ONOO- has also been implicated as playing a role in the pathology of several neurodegenerative disorders, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis, among others. Continuing our laboratory's interest in free radical oxidative stress in brain cells in AD, the present study was designed to investigate the damage to brain neocortical synaptosomal membrane proteins and the oxidation-sensitive enzyme glutamine synthetase (GS) caused by exposure to ONOO-. These synaptosomal proteins and GS have previously been shown by us and others to have been oxidatively damaged in AD brain and also following treatment of synaptosomes with amyloid β-peptide. The results of the current study showed that exposure to physiological levels of ONOO- induced significant protein conformational changes, demonstrated using electron paramagnetic resonance in conjunction with a protein-specific spin label, and caused oxidation of proteins, measured by the increase in protein carbonyls. ONOO- also caused inactivation of GS and led to neuronal cell death examined in a hippocampal cell culture system. All these detrimental effects of ONOO- were successfully attenuated by the thiol-containing antioxidant tripeptide glutathione. This research shows that ONOO- can oxidatively modify both membranous and cytosolic proteins, affecting both their physical and chemical nature. These findings are discussed with reference to the potential involvement of ONOO- in AD neurodegeneration.