PUBLICATION

Protein phosphatase 2A activators reverse age-related behavioral changes by targeting neural cell senescence

Authors
Xing, J., Chen, K., Gao, S., Pousse, M., Ying, Y., Wang, B., Chen, L., Wang, C., Wang, L., Hu, W., Lu, Y., Gilson, E., Ye, J.
ID
ZDB-PUB-230117-4
Date
2023
Source
Aging Cell   22(3): e13780 (Journal)
Registered Authors
Keywords
Age-related cognitive decline, DNA damage response neural senescence, PPP2R2C, protein phosphatase 2A, senolytics, senotherapy
Datasets
GEO:GSE151307
MeSH Terms
  • Models, Animal
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Cognitive Aging*/physiology
  • DNA Damage
  • Behavior, Animal*/drug effects
  • Behavior, Animal*/physiology
  • Neurons*/drug effects
  • Neurons*/enzymology
  • Neurons*/physiology
  • beta-Galactosidase/genetics
  • beta-Galactosidase/metabolism
  • Animals, Genetically Modified
  • Primary Cell Culture
  • Aniline Compounds/pharmacology
  • Brain*/enzymology
  • Cyclin-Dependent Kinase Inhibitor p15/genetics
  • Cyclin-Dependent Kinase Inhibitor p15/metabolism
  • Gene Expression Regulation
  • Senotherapeutics*/pharmacology
  • Gene Knockout Techniques
  • Mutation
  • Biomarkers/metabolism
  • Zebrafish
  • Sulfonamides/pharmacology
  • Cellular Senescence*/drug effects
  • Cellular Senescence*/genetics
  • Cellular Senescence*/physiology
  • Protein Phosphatase 2*/genetics
  • Protein Phosphatase 2*/metabolism
  • Mice
  • Animals
  • Cyclin-Dependent Kinase Inhibitor p16/genetics
  • Cyclin-Dependent Kinase Inhibitor p16/metabolism
(all 34)
PubMed
36644807 Full text @ Aging Cell
Abstract
The contribution of cellular senescence to the behavioral changes observed in the elderly remains elusive. Here, we observed that aging is associated with a decline in protein phosphatase 2A (PP2A) activity in the brains of zebrafish and mice. Moreover, drugs activating PP2A reversed age-related behavioral changes. We developed a transgenic zebrafish model to decrease PP2A activity in the brain through knockout of the ppp2r2c gene encoding a regulatory subunit of PP2A. Mutant fish exhibited the behavioral phenotype observed in old animals and premature accumulation of neural cells positive for markers of cellular senescence, including senescence-associated β-galactosidase, elevated levels cdkn2a/b, cdkn1a, senescence-associated secretory phenotype gene expression, and an increased level of DNA damage signaling. The behavioral and cell senescence phenotypes were reversed in mutant fish through treatment with the senolytic ABT263 or diverse PP2A activators as well as through cdkn1a or tp53 gene ablation. Senomorphic function of PP2A activators was demonstrated in mouse primary neural cells with downregulated Ppp2r2c. We conclude that PP2A reduction leads to neural cell senescence thereby contributing to age-related behavioral changes and that PP2A activators have senotherapeutic properties against deleterious behavioral effects of brain aging.
Genes / Markers
Figures
Figure Gallery (7 images)
Show all Figures
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf4036
    		Small Deletion
    zf4037
      		Small Deletion
      1 - 2 of 2
      Show
      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      cdkn1aCRISPR17-cdkn1aCRISPR
      ppp2r2caCRISPR1-ppp2r2caCRISPR
      1 - 2 of 2
      Show
      Fish
      No data available
      Antibodies
      Name Type Antigen Genes Isotypes Host Organism
      Ab1-ppp2cmonoclonal
        		IgG2bMouse
        Ab1-rbfox3monoclonal
          		IgG1Mouse
          Ab2-rbfox3monoclonal
            		IgGRabbit
            Ab7-h2afxpolyclonal
              		IgGRabbit
              Ab9-h2afxmonoclonal
                		IgGMouse
                Ab11-sox2polyclonal
                  		IgGRabbit
                  Ab22-gfappolyclonal
                    		IgGRabbit
                    1 - 7 of 7
                    Show
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    No data available
                    Mapping
                    No data available
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                    Citation
                    Xing, J., Chen, K., Gao, S., Pousse, M., Ying, Y., Wang, B., Chen, L., Wang, C., Wang, L., Hu, W., Lu, Y., Gilson, E., Ye, J. (2023) Protein phosphatase 2A activators reverse age-related behavioral changes by targeting neural cell senescence. Aging Cell. 22(3):e13780.