A Model for p38MAPK-Induced Astrocyte Senescence

Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers...

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Bibliographic Details
Published in:PloS one 2015-05, Vol.10 (5), p.e0125217-e0125217
Main Authors: Mombach, José C M, Vendrusculo, Bruno, Bugs, Cristhian A
Format: Article
Language:English
Subjects:
Aging
Alzheimer's disease
Analysis
Apoptosis
Apoptosis - genetics
Astrocytes
Astrocytes - cytology
Astrocytes - enzymology
Ataxia
Cancer
Cell cycle
Cell Lineage - genetics
Cellular Senescence
Computer Simulation
Cytokines
Damage
Deoxyribonucleic acid
DNA
DNA damage
Gene Regulatory Networks
Genotype & phenotype
Humans
Kinases
Models, Biological
Molecular modelling
Mutation - genetics
Nervous system
Oxidative stress
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphatase
Physiology
Senescence
Tissues
Variables
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Summary:Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers of senescence in astrocytes from aged brains are increased in brains with Alzheimer's disease. These studies strongly involved the stress kinase p38MAPK in the regulation of the secretory phenotype of astrocytes, yet the molecular mechanisms underlying the onset of senescence and SASP activation remain unclear. In this work, we propose a discrete logical model for astrocyte senescence determined by the level of DNA damage (reparable or irreparable DNA strand breaks) where the kinase p38MAPK plays a central role in the regulation of senescence and SASP. The model produces four alternative stable states: proliferation, transient cycle arrest, apoptosis and senescence (and SASP) computed from its inputs representing DNA damages. Perturbations of the model were performed through gene gain or loss of functions and compared with results concerning cultures of normal and mutant astrocytes showing agreement in most cases. Moreover, the model allows some predictions that remain to be tested experimentally.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0125217