The Role of Oxidative Damage to Nucleic Acids in the Pathogenesis of Neurological Disease
Oxidative stress involving reactive oxygen species (ROS) and reactive nitrogen species (RNS) is integral to the process of aging and age-related diseases such as Alzheimer disease (AD), Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). Oxidative stress-induced modification of nucleic acids impacts on the function of the cell, which can have an important role in the cause of AD. ROS induces hydroxylation of nucleic acid bases (e.g., formation of 8-hydroxy-2' deoxyguanosine (8-OHdG) from deoxyguanosine), and RNS induces their hydroxylative deamination (e.g. cytosine to uracil conversion). 8-OHdG is commonly used as a marker of DNA damage in AD and other age-related diseases, and is approximately 10-fold higher than other oxidized bases. It is present in significant amounts in the mitochondrail and nuclear DNA of AD brains, as compared to control cases. Mitochondrial DNA is relatively more prone to damage as it is exposed to increased concentrations of ROS. In addition to transversion mutations of nucleic acid bases, oxidative stress-induced DNA damage results in delterious DNA-DNA and DNA-protein crosslinking. DNA-DNA crosslinks may also be initiated by RNS-induced deamination of nucleic acid bases. ROS can also modify amyloid-ß, through the oxidation of its constituent methionines to the corresponding radical cations, which initiate free radical chain reactions leading to its aggregation. Nucleic acids are also damaged through the mediation of advanced lipid peroxidation products, such as trans-4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE), which result in the formation of the corresponding “propano-” and “etheno-” adducts. The substantial DNA damage in AD reflects impaired mitochondrial function in the cases of AD, which results in increased ROS/RNS and decreased ATP formation, the latter impacting on the DNA repair.
P. Reddy et al., "The Role of Oxidative Damage to Nucleic Acids in the Pathogenesis of Neurological Disease," Oxidative Damage to Nucleic Acids, pp. 123-140, Landes Bioscience, Jan 2007.
The definitive version is available at http://dx.doi.org/10.1007/978-0-387-72974-9_10
Keywords and Phrases
advanced glycation end products; Alzheimer disease; DNA; HNE; 8-hydroxydeoxyguanosine; nucleic acids; oxidative damage; reactive nitrogen species; reactive oxygen species
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