Regulation of the p19(Arf)/p53 pathway by histone acetylation underlies neural stem cell behavior in senescence-prone SAMP8 mice.
Brain aging is associated with increased neurodegeneration and reduced neurogenesis. B1/neural stem cells (B1-NSCs) of the mouse subependymal zone (SEZ) support the ongoing production of olfactory bulb interneurons, but their neurogenic potential is progressively reduced as mice age. Although age-related changes in B1-NSCs may result from increased expression of tumor suppressor proteins, accumulation of DNA damage, metabolic alterations, and microenvironmental or systemic changes, the ultimate causes remain unclear. Senescence-accelerated-prone mice (SAMP8) relative to senescence-accelerated-resistant mice (SAMR1) exhibit signs of hastened senescence and can be used as a model for the study of aging. We have found that the B1-NSC compartment is transiently expanded in young SAMP8 relative to SAMR1 mice, resulting in disturbed cytoarchitecture of the SEZ, B1-NSC hyperproliferation, and higher yields of primary neurospheres. These unusual features are, however, accompanied by premature loss of B1-NSCs. Moreover, SAMP8 neurospheres lack self-renewal and enter p53-dependent senescence after only two passages. Interestingly, in vitro senescence of SAMP8 cells could be prevented by inhibition of histone acetyltransferases and mimicked in SAMR1 cells by inhibition of histone deacetylases (HDAC). Our data indicate that expression of the tumor suppressor p19, but not of p16, is increased in SAMP8 neurospheres, as well as in SAMR1 neurospheres upon HDAC inhibition, and suggest that the SAMP8 phenotype may, at least in part, be due to changes in chromatin status. Interestingly, acute HDAC inhibition in vivo resulted in changes in the SEZ of SAMR1 mice that resembled those found in young SAMP8 mice.
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Universidad de Valencia, Burjassot, 46100, Spain; Departamento de Biología Celular, Universidad de Valencia, Burjassot, 46100, Spain.
Raúl
R
Soriano-Cantón
Ana
A
Perez-Villalba
José Manuel
JM
Morante-Redolat
María Ángeles
MÁ
Marqués-Torrejón
Mercé
M
Pallás
Francisco
F
Pérez-Sánchez
Isabel
I
Fariñas
D000107:Acetylation; D000375:Aging / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology
C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D006657:Histones
SAMP8 mice; adult neurogenesis; aging; histone acetyltransferases; histone deacetylases; stem cell niche