Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

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). In response to low-level ROS stress, the expression of Delta 133p53, 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 Delta 133p53 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 Delta 133p53 expression. However, it is uncharacterized if Delta 133p53 plays a role in brain aging. Here, we report that zebrafish Delta 113p53, an ortholog of human Delta 133p53, 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 Delta 113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Delta 113p53(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. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Delta 113p53(M/M) zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Delta 113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Delta 113p53/Delta 133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

Automated summary

Delta 133p53 plays a protective role against cellular senescence by upregulating antioxidant genes expression, and its decreased expression in brain tissues of AD and ALS patients has been observed. The zebrafish ortholog Delta 113p53 contributes to neurogenesis and brain function maintenance, with loss of cognitive ability observed in mutants but not in wild-type fish at older ages.