Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease.
DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 x 20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease.
Hoang
Tuan
T
Department of Neurology and Department of Neurobiology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Choi
Dong-Kug
DK
Nagai
Makiko
M
Wu
Du-Chu
DC
Nagata
Tetsuya
T
Prou
Delphine
D
Wilson
Glenn L
GL
Vila
Miquel
M
Jackson-Lewis
Vernice
V
Dawson
Valina L
VL
Dawson
Ted M
TM
Chesselet
Marie-Françoise
MF
Przedborski
Serge
S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000378:metabolism*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013997:Time Factors
D004272:DNA, Mitochondrial; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D052248:Nitric Oxide Synthase Type I; D051546:Cyclooxygenase 2; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases