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

Biomolecules

Joy Mitra¹  Erika N. Guerrero¹  Pavana M. Hegde¹  Haibo Wang¹  Istvan Boldogh³  Kosagi Sharaf Rao²  Sankar Mitra¹ 

[1] Department of Radiation Oncology, Houston Methodist Research Institute, Affiliate of Weill Medical College of Cornell University, 6550 Fannin St, Smith 8-030, Houston, TX 77030, USA; E-Mails:;Centre for Neuroscience, Institute for Scientific Research and Technology Services (INDICASAT-AIP), City of Knowledge, P.O. Box 0843-01103, Panama; E-Mail:;Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; E-Mail:

关键词: redox transition metals;    heavy metals;    DNA base excision repair;    metal toxicity;    metal homeostasis;    neurodegeneration;    Alzheimer’s disease;    Parkinson’s disease;   

DOI  :  10.3390/biom4030678

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.