![]() Δ133p53/Δ113p53 (its zebrafish ortholog) is an N-terminal truncated isoform and a p53 target gene transcribed from an alternative p53 promoter in intron 4 (ref. Human p53 encodes at least 12 isoforms 16, 17. Under low levels of ROS, p53 transcribes antioxidant genes to maintain redox homeostasis and promote cell survival, whereas, in response to high levels of oxidative stress, p53 triggers apoptotic activity by upregulating the expression of pro-oxidative genes and apoptotic genes 11, 13, 14, 15. The signaling pathway of the tumor repressor p53 plays a key role in response to oxidative stress 9, 10, 11, 12. Therefore, the brain becomes prone to oxidative stress that is proposed as a regulatory factor in aging and the progression of multiple neurodegenerative diseases including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) 5, 6, 7, 8. Most neuron cells have a large membrane being enriched in polyunsaturated fatty acids, which are highly susceptible to ROS 4, 5. A large amount of oxygen being consumed in the brain leads to excessive production of ROS. ROS at moderate levels is essential for normal cellular signaling, whereas high levels and long-time exposure of ROS can oxidize cellular macromolecules such as DNA, lipids, and proteins, ultimately resulting in abnormal cell death and senescence 4. ROS is a double-edged sword for cell fate determination. ) and the nonradical species hydrogen peroxide (H 2O 2), are generated endogenously such as in the process of mitochondrial oxidative phosphorylation, or they may arise from interactions with exogenous sources such as xenobiotics, cytokines and bacterial invasion 1, 2, 3.Reactive oxygen species (ROS), such as superoxide anion (O 2 Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53 M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. Importantly, Δ113p53 M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. However, it is uncharacterized if Δ133p53 plays a role in brain aging. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. Reactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS).
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