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Bmi1 is down-regulated in the aging brain and displays antioxidant and protective activities in neurons.

Abdouh M, Chatoo W, El Hajjar J, David J, Ferreira J, Bernier G - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, Montréal, Canada.

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- 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.

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Related in: MedlinePlus

Bmi1 deficiency during aging influences neurons resistance to genotoxic stresses and mitochondrial dysfunctions.Proposed model of Bmi1 function in neurons: (A) When over-expressed, Bmi1 represses p53 activity by an unknown mechanism, leading to complete inhibition of p53 pro-apoptotic and pro-oxidant activities and supra-activation of the antioxidant defense system. (B) In young neurons, where Bmi1 expression is robust, Bmi1 partially represses p53 activity, thus allowing modulation of p53-mediated apoptosis and repression of antioxidant response elements (ARE). These elements are present in antioxidant-coding genes activated by the Nrf2 transcription factor. (C) In aging neurons, where Bmi1 expression becomes deficient, p53 is activated (1), leading to induction of apoptosis and inflammation, and in transcriptional repression of antioxidant-coding genes (2). Elevated mitochondrial reactive oxygen species (mROS) concentrations ultimately induce damages to lipids and DNA, which further activate p53 (3), resulting in the formation of a vicious circle. This situation renders old neurons particularly more vulnerable to genotoxic stresses (gs) and mitochondrial dysfunctions. This model is based on data from the present work, and those published previously [20].
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pone-0031870-g006: Bmi1 deficiency during aging influences neurons resistance to genotoxic stresses and mitochondrial dysfunctions.Proposed model of Bmi1 function in neurons: (A) When over-expressed, Bmi1 represses p53 activity by an unknown mechanism, leading to complete inhibition of p53 pro-apoptotic and pro-oxidant activities and supra-activation of the antioxidant defense system. (B) In young neurons, where Bmi1 expression is robust, Bmi1 partially represses p53 activity, thus allowing modulation of p53-mediated apoptosis and repression of antioxidant response elements (ARE). These elements are present in antioxidant-coding genes activated by the Nrf2 transcription factor. (C) In aging neurons, where Bmi1 expression becomes deficient, p53 is activated (1), leading to induction of apoptosis and inflammation, and in transcriptional repression of antioxidant-coding genes (2). Elevated mitochondrial reactive oxygen species (mROS) concentrations ultimately induce damages to lipids and DNA, which further activate p53 (3), resulting in the formation of a vicious circle. This situation renders old neurons particularly more vulnerable to genotoxic stresses (gs) and mitochondrial dysfunctions. This model is based on data from the present work, and those published previously [20].

Mentions: The contexts of Bmi1 deficiency in mice (which leads to a severe and early lethal pathology) and of physiological aging are completely different. Hence, it is most unexpected that Bmi1 down-regulation in neurons during brain physiological aging leads to a molecular phenotype that resembles Bmi1 genetic deficiency. The apparent conservation of the Bmi1-p53 antioxidant relationship during physiological aging is thus an important finding that brings new knowledge on the mechanisms regulating the process of physiological aging in the central nervous system. Our previous findings provided a molecular mechanism to explain why Bmi1- neurons age prematurely and are hypersensitive to various stressors [20]. Considering Bmi1 down-regulation in the aging central nervous system, this may also explain why aged neurons are more sensitive to various insults. Cellular and DNA damage produced by mitochondrial ROS have been proposed to be the causal factor of cellular and organismal aging [1], [3], [7]. Herein we observed that p53 accumulates at AOR gene promoters in the aging mouse brain, correlating with reduced AOR genes expression. This suggests that deficient BMI1 expression in the human brain may contribute to reduce antioxidant defenses, leading to accumulation of oxidative damage and neuronal dysfunction. Although controversial, neuroinflammation is potentially a driving force of normal brain aging and neurodegenerative diseases. The cytokine IL-6 is a biomarker of brain aging, and high levels of IL-6 are found in senescent cells and Alzheimer disease brains [25], [48]. We found that old and Bmi1−/− brains expressed high levels of IL-6, and that this was p53-dependent in cultured Bmi1−/− neurons. These observations suggest that Bmi1 deficiency during aging could amplify p53 activity and thus accelerate the process of normal brain aging and age-related neurological diseases in readily susceptible individuals (see proposed model in Figure 6). Finally, while increased p53 activity in aging neurons may be in part explained by the loss of Bmi1 expression, the age-associated mechanism leading to Bmi1 down-regulation remains to be investigated. Although this mechanism apparently operates at the transcriptional level, as reported for other genes in the aging brain [1], age-dependent Bmi1 mRNA degradation through specific miRNA activity is possible [49]. Also, it cannot be excluded that activated p53 represses Bmi1 transcription, although such evidences do not exist yet. At last, Bmi1 protein may be also preferentially targeted for degradation in aging neurons [50], [51], [52]. In old mice, Bmi1 expression declined only in neurons, not in astrocytes. Notably, only astrocytes have the potential to generate tumors. These data indicate that down-regulation of the Bmi1 oncogene in neurons during aging is apparently not a general response to prevent cancer (at least in mice). Rather, it may represent an epigenetic change related to normal brain aging [1]. Taken together, our work suggests that targeted pharmaceutical stimulation of Bmi1 expression in aging neurons could prevent accumulation of age-associated oxidative damages, protect against apoptosis and possibly counteract the progression of neurodegenerative diseases.


Bmi1 is down-regulated in the aging brain and displays antioxidant and protective activities in neurons.

Abdouh M, Chatoo W, El Hajjar J, David J, Ferreira J, Bernier G - PLoS ONE (2012)

Bmi1 deficiency during aging influences neurons resistance to genotoxic stresses and mitochondrial dysfunctions.Proposed model of Bmi1 function in neurons: (A) When over-expressed, Bmi1 represses p53 activity by an unknown mechanism, leading to complete inhibition of p53 pro-apoptotic and pro-oxidant activities and supra-activation of the antioxidant defense system. (B) In young neurons, where Bmi1 expression is robust, Bmi1 partially represses p53 activity, thus allowing modulation of p53-mediated apoptosis and repression of antioxidant response elements (ARE). These elements are present in antioxidant-coding genes activated by the Nrf2 transcription factor. (C) In aging neurons, where Bmi1 expression becomes deficient, p53 is activated (1), leading to induction of apoptosis and inflammation, and in transcriptional repression of antioxidant-coding genes (2). Elevated mitochondrial reactive oxygen species (mROS) concentrations ultimately induce damages to lipids and DNA, which further activate p53 (3), resulting in the formation of a vicious circle. This situation renders old neurons particularly more vulnerable to genotoxic stresses (gs) and mitochondrial dysfunctions. This model is based on data from the present work, and those published previously [20].
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3285640&req=5

pone-0031870-g006: Bmi1 deficiency during aging influences neurons resistance to genotoxic stresses and mitochondrial dysfunctions.Proposed model of Bmi1 function in neurons: (A) When over-expressed, Bmi1 represses p53 activity by an unknown mechanism, leading to complete inhibition of p53 pro-apoptotic and pro-oxidant activities and supra-activation of the antioxidant defense system. (B) In young neurons, where Bmi1 expression is robust, Bmi1 partially represses p53 activity, thus allowing modulation of p53-mediated apoptosis and repression of antioxidant response elements (ARE). These elements are present in antioxidant-coding genes activated by the Nrf2 transcription factor. (C) In aging neurons, where Bmi1 expression becomes deficient, p53 is activated (1), leading to induction of apoptosis and inflammation, and in transcriptional repression of antioxidant-coding genes (2). Elevated mitochondrial reactive oxygen species (mROS) concentrations ultimately induce damages to lipids and DNA, which further activate p53 (3), resulting in the formation of a vicious circle. This situation renders old neurons particularly more vulnerable to genotoxic stresses (gs) and mitochondrial dysfunctions. This model is based on data from the present work, and those published previously [20].
Mentions: The contexts of Bmi1 deficiency in mice (which leads to a severe and early lethal pathology) and of physiological aging are completely different. Hence, it is most unexpected that Bmi1 down-regulation in neurons during brain physiological aging leads to a molecular phenotype that resembles Bmi1 genetic deficiency. The apparent conservation of the Bmi1-p53 antioxidant relationship during physiological aging is thus an important finding that brings new knowledge on the mechanisms regulating the process of physiological aging in the central nervous system. Our previous findings provided a molecular mechanism to explain why Bmi1- neurons age prematurely and are hypersensitive to various stressors [20]. Considering Bmi1 down-regulation in the aging central nervous system, this may also explain why aged neurons are more sensitive to various insults. Cellular and DNA damage produced by mitochondrial ROS have been proposed to be the causal factor of cellular and organismal aging [1], [3], [7]. Herein we observed that p53 accumulates at AOR gene promoters in the aging mouse brain, correlating with reduced AOR genes expression. This suggests that deficient BMI1 expression in the human brain may contribute to reduce antioxidant defenses, leading to accumulation of oxidative damage and neuronal dysfunction. Although controversial, neuroinflammation is potentially a driving force of normal brain aging and neurodegenerative diseases. The cytokine IL-6 is a biomarker of brain aging, and high levels of IL-6 are found in senescent cells and Alzheimer disease brains [25], [48]. We found that old and Bmi1−/− brains expressed high levels of IL-6, and that this was p53-dependent in cultured Bmi1−/− neurons. These observations suggest that Bmi1 deficiency during aging could amplify p53 activity and thus accelerate the process of normal brain aging and age-related neurological diseases in readily susceptible individuals (see proposed model in Figure 6). Finally, while increased p53 activity in aging neurons may be in part explained by the loss of Bmi1 expression, the age-associated mechanism leading to Bmi1 down-regulation remains to be investigated. Although this mechanism apparently operates at the transcriptional level, as reported for other genes in the aging brain [1], age-dependent Bmi1 mRNA degradation through specific miRNA activity is possible [49]. Also, it cannot be excluded that activated p53 represses Bmi1 transcription, although such evidences do not exist yet. At last, Bmi1 protein may be also preferentially targeted for degradation in aging neurons [50], [51], [52]. In old mice, Bmi1 expression declined only in neurons, not in astrocytes. Notably, only astrocytes have the potential to generate tumors. These data indicate that down-regulation of the Bmi1 oncogene in neurons during aging is apparently not a general response to prevent cancer (at least in mice). Rather, it may represent an epigenetic change related to normal brain aging [1]. Taken together, our work suggests that targeted pharmaceutical stimulation of Bmi1 expression in aging neurons could prevent accumulation of age-associated oxidative damages, protect against apoptosis and possibly counteract the progression of neurodegenerative diseases.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont, Montréal, Canada.

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- 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.

Show MeSH
Related in: MedlinePlus