|ZFIN ID: ZDB-PUB-210207-2|
Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish
Zhao, T., Ye, S., Tang, Z., Guo, L., Ma, Z., Zhang, Y., Yang, C., Peng, J., Chen, J.
|Source:||Cell Death & Disease 12: 151 (Journal)|
|Registered Authors:||Chen, Jun, Peng, Jinrong|
|PubMed:||33542214 Full text @ Cell Death Dis.|
Zhao, T., Ye, S., Tang, Z., Guo, L., Ma, Z., Zhang, Y., Yang, C., Peng, J., Chen, J. (2021) Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish. Cell Death & Disease. 12:151.
ABSTRACTReactive 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). 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. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. 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. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/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. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. 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.