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, p19Arf and p16Ink4a, 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.
Highlights
Aging is the prime risk factor for the development of several neurodegenerative diseases
Using whole cerebral extracts and quantitative RT-PCR (Q-PCR), we found that Bmi1 mRNA levels decrease by,60% in old cortices, suggesting reduced Bmi1 transcription (Figure 1B)
We presented evidences that BMI1 overexpression is neuroprotective, can activate antioxidant response (AOR) genes, and can suppress reactive oxygen species (ROS)
Summary
Aging is the prime risk factor for the development of several neurodegenerative diseases. Long lived neuronal cells are more likely to accumulate mutations in their genomic DNA than most other cell types with age, leading to impaired cellular functions [2,3]. This phenomenon may be explain in part due to the inability of post-mitotic cells to replicate their DNA, a process that is tightly coupled to DNA damage checkpoint and DNA repair [4,5,6]. The balance between ROS and antioxidant molecules is critical to determine the rate of oxidative damage accumulation, and possibly cellular and organism lifespan [9]. Reduced antioxidant response (AOR) genes expression in the aging brain could displace the oxidative balance and may instigate accelerated aging and age-related neurodegenerative diseases
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