title: The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity.
abstract: Aging may be determined by a genetic program and/or by the accumulation rate of molecular damages. Reactive oxygen species (ROS) generated by the mitochondrial metabolism have been postulated to be the central source of molecular damages and imbalance between levels of intracellular ROS and antioxidant defenses is a characteristic of the aging brain. How aging modifies free radicals concentrations and increases the risk to develop most neurodegenerative diseases is poorly understood, however. Here we show that the Polycomb group and oncogene Bmi1 is required in neurons to suppress apoptosis and the induction of a premature aging-like program characterized by reduced antioxidant defenses. Before weaning, Bmi1(-/-) mice display a progeroid-like ocular and brain phenotype, while Bmi1(+/-) mice, although apparently normal, have reduced lifespan. Bmi1 deficiency in neurons results in increased p19(Arf)/p53 levels, abnormally high ROS concentrations, and hypersensitivity to neurotoxic agents. Most Bmi1 functions on neurons' oxidative metabolism are genetically linked to repression of p53 pro-oxidant activity, which also operates in physiological conditions. In Bmi1(-/-) neurons, p53 and corepressors accumulate at antioxidant gene promoters, correlating with a repressed chromatin state and antioxidant gene downregulation. These findings provide a molecular mechanism explaining how Bmi1 regulates free radical concentrations and reveal the biological impact of Bmi1 deficiency on neuronal survival and aging.
authors.affiliation: Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
authors.forename: Wassim
authors.initials: W
authors.lastname: Chatoo
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdouh
authors.forename: Jocelyn
authors.initials: J
authors.lastname: David
authors.forename: Marie-Pier
authors.initials: MP
authors.lastname: Champagne
authors.forename: José
authors.initials: J
authors.lastname: Ferreira
authors.forename: Francis
authors.initials: F
authors.lastname: Rodier
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bernier
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; D005136:Eye Proteins; D005904:Glial Fibrillary Acidic Protein; D006657:Histones; D018398:Homeodomain Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009498:Neurotoxins; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D063150:Polycomb Repressive Complex 1; D001616:beta-Galactosidase; D010751:Phosphopyruvate Hydratase