Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish.
Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish.
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p53亚型α113p53的功能丧失会加速斑马鱼的大脑衰老。
DOI：
10.1038/s41419-021-03438-9
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发表时间：
2021-02-04
影响因子：
9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Zhao T;Ye S;Tang Z;Guo L;Ma Z;Zhang Y;Yang C;Peng J;Chen J
活性氧（ROS）应激已被证明对诱导和维持细胞衰老具有潜在的关键作用，并被认为是衰老和各种神经系统疾病（包括阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS））的影响因素。响应低水平的 ROS 应激，人类 p53 亚型 Δ133p53 的表达上调，通过增强抗氧化基因的表达来促进细胞存活并保护细胞免于衰老。在正常情况下，Δ133p53 的基础表达可防止人成纤维细胞、T 淋巴细胞和星形胶质细胞复制性衰老。研究还发现，AD 和 ALS 患者的脑组织中 Δ133p53 表达减少。然而，Δ133p53 是否在大脑衰老中发挥作用尚不清楚。在此，我们报道斑马鱼Δ113p53是人类Δ133p53的直系同源物，主要以全长p53依赖性方式在沿端脑心室区的一些放射状胶质细胞中表达。 EDU 标记和细胞谱系追踪表明，Δ113p53 阳性细胞经历细胞增殖，有助于神经元更新过程。重要的是，自 9 个月大起，Δ113p53M/M 突变体端脑与野生型（WT）斑马鱼端脑相比，具有较少的增殖细胞和更多的衰老细胞，这与突变体端脑中抗氧化基因表达的减少和 ROS 水平的增加有关。更有趣的是，与5个月大时具有认知能力的突变鱼不同，Δ113p53M/M斑马鱼（而非WT斑马鱼）在19个月大时就失去了学习和记忆能力。结果表明，Δ113p53 通过其抗氧化功能保护大脑免于衰老。我们的发现提供了生物体水平的证据，表明Δ113p53/Δ133p53的消耗可能导致长期的ROS应激，并最终导致与年龄相关的疾病，例如人类的AD和ALS。
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.
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影响因子：
16.2
作者：
Herskovits AZ;Guarente L
通讯作者：
Guarente L
Def 磷酸化通过 Def 募集 Calpain3 调节核仁 p53 周转和细胞周期进展
影响因子：
9.8
作者：
Guan Y;Huang D;Chen F;Gao C;Tao T;Shi H;Zhao S;Liao Z;Lo LJ;Wang Y;Chen J;Peng J
通讯作者：
Peng J
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.5
作者：
Kishimoto, Norihito;Alfaro-Cervello, Clara;Sawamoto, Kazunobu
通讯作者：
Sawamoto, Kazunobu
DOI：
10.1073/pnas.0406252102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Berghmans, S;Murphey, RD;Look, AT
通讯作者：
Look, AT