Oxidative stress

About: Oxidative stress is a research topic. Over the lifetime, 86513 publications have been published within this topic receiving 3845790 citations. The topic is also known as: oxydative stress.

Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production

Abstract: The mitochondrial theory of aging proposes that reactive oxygen species (ROS) generated inside the cell will lead, with time, to increasing amounts of oxidative damage to various cell components. The main site for ROS production is the respiratory chain inside the mitochondria and accumulation of mtDNA mutations, and impaired respiratory chain function have been associated with degenerative diseases and aging. The theory predicts that impaired respiratory chain function will augment ROS production and thereby increase the rate of mtDNA mutation accumulation, which, in turn, will further compromise respiratory chain function. Previously, we reported that mice expressing an error-prone version of the catalytic subunit of mtDNA polymerase accumulate a substantial burden of somatic mtDNA mutations, associated with premature aging phenotypes and reduced lifespan. Here we show that these mtDNA mutator mice accumulate mtDNA mutations in an approximately linear manner. The amount of ROS produced was normal, and no increased sensitivity to oxidative stress-induced cell death was observed in mouse embryonic fibroblasts from mtDNA mutator mice, despite the presence of a severe respiratory chain dysfunction. Expression levels of antioxidant defense enzymes, protein carbonylation levels, and aconitase enzyme activity measurements indicated no or only minor oxidative stress in tissues from mtDNA mutator mice. The premature aging phenotypes in mtDNA mutator mice are thus not generated by a vicious cycle of massively increased oxidative stress accompanied by exponential accumulation of mtDNA mutations. We propose instead that respiratory chain dysfunction per se is the primary inducer of premature aging in mtDNA mutator mice.

Proteomic identification of nitrated proteins in Alzheimer's disease brain.

Abstract: 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 O � : 2 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

Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS

Abstract: Transgenic mice that highly over-express a mutated human CuZn superoxide dismutase (SOD1) gene [gly93-->ala; TgN(SOD1-G93A)G1H line] found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease that is characterized by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of motor activity. The mutant Cu,Zn SOD exhibits essentially normal SOD activity but also generates toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. Consequently, lipid and protein oxidative damage to the spinal motor neurons occurs and is associated with disease onset and progression. In the present study, we investigated the time course of microglial (major histocompatibility-II antigen immunoreactivity) and astrocytic (glial fibrillary acidic protein immunoreactivity) activation in relation to the course of motor neuron disease in the TgN(SOD1-G93A)G1H FALS mice. Four ages were investigated: 30 days (pre-motor neuron pathology and clinical disease); 60 days (after initiation of pathology, but pre-disease); 100 days (approximately 50% loss of motor neurons and function); and 120 days (near complete hindlimb paralysis). Compared to non-transgenic littermates, the TgN(SOD1-G93A)G1H mice showed significantly increased numbers of activated astrocytes (P < 0.01) at 100 days of age in both the cervical and lumbar spinal cord regions. However, at 120 days of age, the activation lost statistical significance. In contrast, microglial activation was significantly increased several-fold at both 100 and 120 days. We hypothesize that astrocytic activation may exert a trophic influence on the motor neurons that is insufficiently maintained late in the course of the disease. On the other hand, the sustained, intense microglial activation may conceivably contribute to the oxidative stress and damage involved in the disease process. If true, then agents which inhibit microglia may help to limit disease progression.