DNA damage in brain mitochondria caused by aging and MPTP treatment.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment leads to marked depletion of dopamine (DA) levels in the nigrostriatal pathway and dopaminergic neuronal degeneration in caudate-putamen and substantia nigra. MPTP is believed to inhibit complex I of the electron transport system leading to the generation of reactive oxygen species. We sought to test the hypotheses that MPTP treatment: (1) leads to dopamine depletion; (2) causes extensive mitochondrial DNA damage, and (3) that these effects would be age dependent. The levels of dopamine and its metabolites, DOPAC and HVA were analyzed by HPLC equipped with electrochemical detection. DNA damage was measured by quantitative PCR in both mitochondrial and nuclear (beta-polymerase) targets from the caudate-putamen, substantia nigra and cerebellum regions of control and MPTP-treated mice. The age groups studied were 22 days and 12 months. MPTP produced no significant effect on the levels of dopamine and its metabolites in young mice whereas in old, there was a significant decrease in this neurotransmitter system after MPTP administration. These 12-month-old mice, when compared to the young mice, showed a significant increase in mitochondrial DNA damage in the caudate-putamen and cerebellum. The latter region also displayed a significant increase in DNA damage in a nuclear gene. After treatment with MPTP, there was an age-dependent increase in DNA damage in mitochondria of the caudate-putamen while there was no significant DNA damage in the nuclear target. MPTP treatment led to damage in both mitochondrial and nuclear DNA of the substantia nigra, while there was no damage in either mitochondria or nucleus in cerebellum which was used as a negative control.
Mandavilli
B S
BS
Laboratory of Molecular Genetics, National Institute of Environmental and Health Sciences, 111 Alexander Drive, Box 12233, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Ali
S F
SF
Van Houten
B
B
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000367:Age Factors; D000375:Aging / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D004249:DNA Damage / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D004298:Dopamine / Q000032:analysis; D006719:Homovanillic Acid / Q000032:analysis; D020267:MPTP Poisoning / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics
D004272:DNA, Mitochondrial; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid