Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis.
Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a transcription factor belonging to the superfamily of nuclear receptors. Disruption of the Rora gene in the mouse results in a defect in the development of Purkinje cells leading to a cerebellar atrophy, which suggests a neuroprotective role for RORalpha. To test this hypothesis, the survival rate of lentiviral-mediated human RORalpha1-overexpressing neurones has been evaluated in response to different stressors disturbing the redox homeostasis, such as beta-amyloid peptide, c(2)-ceramide and H(2)O(2). We show that overexpression of human RORalpha1 provides neuroprotection by increasing the expression of the antioxidant proteins glutathione peroxidase 1 and peroxiredoxin 6, leading to a reduction in the accumulation of stress-induced reactive oxygen species. We further demonstrate that the neuroprotective effect of RORalpha is predominantly mediated by glutathione peroxidase 1 and peroxiredoxin 6. These results suggest a new role for RORalpha in the control of the neuronal oxidative stress and thus represents a new transcription factor of interest in the regulation of reactive oxygen species-induced neurodegenerative processes during ageing.
Université Pierre et Marie Curie-Paris 6, UMR 7102, Neurobiologie des Processus Adaptifs CNRS, Paris, France. Fatiha.Boukhtouche@snv.jussieu.fr
Fatiha
F
Boukhtouche
Guilan
G
Vodjdani
Christopher I
CI
Jarvis
Joelle
J
Bakouche
Bart
B
Staels
Jacques
J
Mallet
Jean
J
Mariani
Yolande
Y
Lemaigre-Dubreuil
Bernard
B
Brugg
D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018384:Oxidative Stress / Q000502:physiology*; D010544:Peroxidases / Q000378:metabolism; D054465:Peroxiredoxin VI; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D015534:Trans-Activators; D014162:Transfection; D000094765:Glutathione Peroxidase GPX1
D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; C539739:Rora protein, mouse; D015534:Trans-Activators; D010544:Peroxidases; C515977:PRDX6 protein, human; D054465:Peroxiredoxin VI; D054464:Peroxiredoxins; C515983:Prdx6 protein, mouse; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1