title: A Model for p38MAPK-Induced Astrocyte Senescence.
abstract: 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.
authors.affiliation: Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: José C M
authors.initials: JC
authors.lastname: Mombach
authors.affiliation: Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vendrusculo
authors.affiliation: Universidade Federal do Pampa, São Gabriel, RS, Brazil.
authors.forename: Cristhian A
authors.initials: CA
authors.lastname: Bugs
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000166:cytology* / Q000201:enzymology*; D019070:Cell Lineage / Q000235:genetics; D016922:Cellular Senescence; D003198:Computer Simulation; D053263:Gene Regulatory Networks; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases