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The Journal of Neuroscience, January 14, 2009, 29(2):529-542; doi:10.1523/JNEUROSCI.5303-08.2009

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Neurobiology of Disease
The Polycomb Group Gene Bmi1 Regulates Antioxidant Defenses in Neurons by Repressing p53 Pro-Oxidant Activity

Wassim Chatoo,^1 * Mohamed Abdouh,^1 * Jocelyn David,¹ Marie-Pier Champagne,¹ José Ferreira,² Francis Rodier,⁴ and Gilbert Bernier^1,3

¹Developmental Biology Laboratory and ²Department of Pathology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada H1T 2M4, ³Department of Ophthalmology, University of Montreal, Montreal, Quebec, Canada H3T 1J4, and ⁴Lawrence Berkeley National Laboratory, Berkeley, California 94720

Correspondence should be addressed to Gilbert Bernier, Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boulevard de l'Assomption, Montreal, Quebec, Canada H1T 2M4. Email: gbernier.hmr{at}ssss.gouv.qc.ca

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.

Key words: Bmi1; p53; neuronal cell death; ROS; antioxidant; aging

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Received Nov. 4, 2008; accepted Dec. 2, 2008.

Correspondence should be addressed to Gilbert Bernier, Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boulevard de l'Assomption, Montreal, Quebec, Canada H1T 2M4. Email: gbernier.hmr{at}ssss.gouv.qc.ca

This article has been cited by other articles:

				M. Abdouh, S. Facchino, W. Chatoo, V. Balasingam, J. Ferreira, and G. Bernier BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal J. Neurosci., July 15, 2009; 29(28): 8884 - 8896. [Abstract] [Full Text] [PDF]

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