title: Bmi1 is down-regulated in the aging brain and displays antioxidant and protective activities in neurons.
abstract: Aging increases the risk to develop several neurodegenerative diseases, although the underlying mechanisms are poorly understood. Inactivation of the Polycomb group gene Bmi1 in mice results in growth retardation, cerebellar degeneration, and development of a premature aging-like phenotype. This progeroid phenotype is characterized by formation of lens cataracts, apoptosis of cortical neurons, and increase of reactive oxygen species (ROS) concentrations, owing to p53-mediated repression of antioxidant response (AOR) genes. Herein we report that Bmi1 expression progressively declines in the neurons of aging mouse and human brains. In old brains, p53 accumulates at the promoter of AOR genes, correlating with a repressed chromatin state, down-regulation of AOR genes, and increased oxidative damages to lipids and DNA. Comparative gene expression analysis further revealed that aging brains display an up-regulation of the senescence-associated genes IL-6, p19(Arf) and p16(Ink4a), along with the pro-apoptotic gene Noxa, as seen in Bmi1-null mice. Increasing Bmi1 expression in cortical neurons conferred robust protection against DNA damage-induced cell death or mitochondrial poisoning, and resulted in suppression of ROS through activation of AOR genes. These observations unveil that Bmi1 genetic deficiency recapitulates aspects of physiological brain aging and that Bmi1 over-expression is a potential therapeutic modality against neurodegeneration.
authors.affiliation: Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, Montréal, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdouh
authors.forename: Wassim
authors.initials: W
authors.lastname: Chatoo
authors.forename: Jida
authors.initials: J
authors.lastname: El Hajjar
authors.forename: Jocelyn
authors.initials: J
authors.lastname: David
authors.forename: José
authors.initials: J
authors.lastname: Ferreira
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bernier
mesh_terms: D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D015227:Lipid Peroxidation; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000517:prevention & control; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000975:Antioxidants; C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; D002843:Chromatin; D008055:Lipids; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; D063150:Polycomb Repressive Complex 1