New Perspectives on Oxidized Genome Damage and Repair Inhibition by Pro-Oxidant Metals in Neurological Diseases

Abstract

The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region(s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases.

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

“…Seminal work by Graf and associates demonstrated that the availability of only one of the six coordination sites is sufficient to render the iron atom redox active, namely capable of catalyzing the production of hydroxyl radicals by Fenton chemistry (Graf et al, 1984). Increased levels of iron promote neurotoxicity through hydroxyl radical formation, glutathione consumption, protein aggregation, lipid peroxidation, nucleic acid modification, and reduced DNA repair activity (Farina et al, 2013;Jomova et al, 2010;Mitra et al, 2014;Nunez et al, 2004).…”

In VitroIon Chelating, Antioxidative Mechanism of Extracts from Fruits and Barks ofTetrapleura tetrapteraand Their Protective Effects against Fenton Mediated Toxicity of Metal Ions on Liver Homogenates

“…Several fundamental life functions such as enzymatic catalyzed reactions heavily rely on metal ions [1]. Metal ions are indispensable for cells metabolism in trace; however, in a higher quantity, they could be toxic for human.…”

The Extracellular Domain of Human High Affinity Copper Transporter (hNdCTR1), Synthesized by<em> E. coli</em> Cells, Chelates Silver and Copper Ions <em>in Vivo</em>

“…It can be released when the structure of these proteins is damaged [18]. Therefore, copper chelators are considered as a promising therapeutic agent to scavenge of free copper ions in the extra-and intracellular spaces [11,[19][20][21][22].…”