Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease.

Published

Journal Article

DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the role of mitochondrial DNA (mtDNA) damage in human postmortem brain tissue and in in vivo and in vitro models of PD, using a newly adapted histochemical assay for abasic sites and a quantitative polymerase chain reaction (QPCR)-based assay. We identified the molecular identity of mtDNA damage to be apurinic/apyrimidinic (abasic) sites in substantia nigra dopamine neurons, but not in cortical neurons from postmortem PD specimens. To model the systemic mitochondrial impairment of PD, rats were exposed to the pesticide rotenone. After rotenone treatment that does not cause neurodegeneration, abasic sites were visualized in nigral neurons, but not in cortex. Using a QPCR-based assay, a single rotenone dose induced mtDNA damage in midbrain neurons, but not in cortical neurons; similar results were obtained in vitro in cultured neurons. Importantly, these results indicate that mtDNA damage is detectable prior to any signs of degeneration - and is produced selectively in midbrain neurons under conditions of mitochondrial impairment. The selective vulnerability of midbrain neurons to mtDNA damage was not due to differential effects of rotenone on complex I since rotenone suppressed respiration equally in midbrain and cortical neurons. However, in response to complex I inhibition, midbrain neurons produced more mitochondrial H2O2 than cortical neurons. We report selective mtDNA damage as a molecular marker of vulnerable nigral neurons in PD and suggest that this may result from intrinsic differences in how these neurons respond to complex I defects. Further, the persistence of abasic sites suggests an ineffective base excision repair response in PD.

Full Text

Duke Authors

Cited Authors

  • Sanders, LH; McCoy, J; Hu, X; Mastroberardino, PG; Dickinson, BC; Chang, CJ; Chu, CT; Van Houten, B; Greenamyre, JT

Published Date

  • October 2014

Published In

Volume / Issue

  • 70 /

Start / End Page

  • 214 - 223

PubMed ID

  • 24981012

Pubmed Central ID

  • 24981012

Electronic International Standard Serial Number (EISSN)

  • 1095-953X

Digital Object Identifier (DOI)

  • 10.1016/j.nbd.2014.06.014

Language

  • eng

Conference Location

  • United States