Oxidative genome damage and its repair in neurodegenerative diseases: Function of transition metals as a double-edged sword

Muralidhar L. Hegde, Pavana M. Hegde, K. S. Rao, Sankar Mitra

Research output: Contribution to journalReview article

45 Scopus citations

Abstract

The neurons in the central nervous system (CNS) with high O2 consumption and prolonged life span are chronically exposed to high levels of reactive oxygen species (ROS). Accumulation of ROS-induced genome damage in the form of oxidized bases and single-strand breaks (SSBs) as well as their defective or reduced repair in the brain has been implicated in the etiology of various neurological disorders including Alzheimer's/Parkinson's diseases (AD/PD). Although inactivating mutations in some DNA repair genes have been linked to hereditary neurodegenerative diseases, the underlying mechanisms of repair deficiencies for the sporadic diseases is not understood. The ROS-induced DNA damage is predominantly repaired via the highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that the transition metals iron and copper, which accumulate excessively in the brains of AD, PD, and other neurodegenerative diseases, act as a 'double-edged sword' by inducing genotoxic ROS and inhibiting DNA damage repair at the same time. These metals inhibit the base excision activity of NEIL family DNA glycosylases by oxidizing them, changing their structure, and inhibiting their binding to downstream repair proteins. Metal chelators and reducing agents partially reverse the inhibition, while curcumin with both chelating and reducing activities reverses the inhibition nearly completely. In this review, we have discussed the possible etiological linkage of BER/SSBR defects to neurodegenerative diseases and the therapeutic potential of metal chelators in restoring DNA repair capacity.

Original languageEnglish (US)
Pages (from-to)183-198
Number of pages16
JournalJournal of Alzheimer's Disease
Volume24
Issue numberSUPPL. 2
DOIs
StatePublished - 2011

Keywords

  • Alzheimer's disease
  • base excision repair
  • curcumin
  • metal chelators
  • metal toxicity
  • neurodegenerative diseases
  • oxidative genome damage
  • Parkinson's disease

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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