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

Abstract

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 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.

Role of Reactive Oxygen Species in Aging and Age-Related Diseases: A Review

“…163 Δ133p53 is a protein that preserves cells from senescence through the enhancement of antioxidant gene expression. 164 An animal study on zebrafish showed that depletion of Δ113p53/Δ133p53 causes long-term ROS stress, which accelerates the aging process through age-related diseases, such as AD and ALS in humans. 164 One of the major indications of Alzheimer's disease (AD) is amyloid-beta (Aβ) peptide buildup in the mitochondria, which leads to ROS formation enhanced by metal ions such as Fe 2+ and Cu 2+ .…”

“…164 An animal study on zebrafish showed that depletion of Δ113p53/Δ133p53 causes long-term ROS stress, which accelerates the aging process through age-related diseases, such as AD and ALS in humans. 164 One of the major indications of Alzheimer's disease (AD) is amyloid-beta (Aβ) peptide buildup in the mitochondria, which leads to ROS formation enhanced by metal ions such as Fe 2+ and Cu 2+ . 165 In this regard, carbohydrate modification, lipid peroxidation, oxidation of protein (DNA/RNA), and the creation of free radicals by Aβ itself are all possible mechanisms for causing oxidative stress.…”

“…The accumulation of lipid-based ROS causes iron-dependent cell death termed Ferroptosis. , It has been suggested as the fundamental operator of neurological cell death in AD . Δ133p53 is a protein that preserves cells from senescence through the enhancement of antioxidant gene expression . An animal study on zebrafish showed that depletion of Δ113p53/Δ133p53 causes long-term ROS stress, which accelerates the aging process through age-related diseases, such as AD and ALS in humans …”

“…Δ133p53 is a protein that preserves cells from senescence through the enhancement of antioxidant gene expression . An animal study on zebrafish showed that depletion of Δ113p53/Δ133p53 causes long-term ROS stress, which accelerates the aging process through age-related diseases, such as AD and ALS in humans …”

Adaptive homeostasis and the p53 isoform network

“…Using mouse and zebrafish models, several studies have demonstrated that the regenerative capacity of neural precursor and axon regeneration is regulated by altering the p53 isoform ratio. During ageing, this regulatory mechanism deteriorates, resulting in disruptions in the ability of stem cells to proliferate leading to neurodegeneration (Medrano et al , 2009 ; Ungewitter & Scrable, 2010 ; Takahashi et al , 2013 ; Zhao et al , 2021 ). Interestingly, as in heart regeneration, the MDM2 pathway controls p53 network activity in axonal regeneration, sprouting and functional recovery after brain injury (Joshi et al , 2015 ).…”