Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice.
Knocking out of Nurr1 gene, a member of nuclear receptor superfamily, causes selective agenesis of dopaminergic neurons in midbrain. Reduced expression of Nurr1 increases the vulnerability of mesencephalic dopamine neurons to dopaminergic toxins. We evaluated the role of nitric oxide as a possible mechanism for this increased susceptibility. Increased expression of neuronal nitric oxide synthase and increased 3-nitrotyrosine were observed in striatum of Nurr1 heterozygous (Nurr1 +/-) mice as compared with wild-type. Increased cytochrome C activation and consecutive release of Smac/DIABLO were also observed in Nurr1 +/- mice. An induction of active Caspase-3 and p53, cleavage of poly-ADP (RNase) polymerase and reduced expression of bcl-2 were observed in Nurr1 +/- mice. Methamphetamine significantly increased these markers in Nurr1 +/- mice as compared with wild-type. The present data therefore suggest that nitric oxide plays a role as a modulating factor for the increased susceptibility, but not the potentiation, of the dopaminergic terminals in Nurr1 +/- mice. We also report that this increased neuronal nitric oxide synthase expression and increased nitration in Nurr1 +/- mice led to the activation of apoptotic cascade via the differential alterations in the DNA binding activity of transcription factors responsible for the propagation of growth arrest as well as apoptosis.
Imam
Syed Z
SZ
South Texas Veteran Health Care System and Department of Medicine of UT Health Science, San Antonio, Texas, USA. simam@satx.rr.com
Jankovic
Joseph
J
Ali
Syed F
SF
Skinner
John T
JT
Xie
Wenjie
W
Conneely
Orla M
OM
Le
Wei-Dong
WD
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D045304:Cytochromes c / Q000032:analysis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000235:genetics; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051844:alpha-Synuclein / Q000378:metabolism; D051020:bcl-X Protein / Q000032:analysis
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C499605:Diablo protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D024101:Mitochondrial Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051844:alpha-Synuclein; D051020:bcl-X Protein; D009569:Nitric Oxide; D008694:Methamphetamine; D045304:Cytochromes c; D052248:Nitric Oxide Synthase Type I