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Title: | A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers |
Author: | Torres, Pascual Anerillas, Carlos Ramírez Núñez, Omar Fernàndez, Anna Encinas, Mario Povedano, Mònica Andrés Benito, Pol Ferrer, Isidro (Ferrer Abizanda) Ayala, Victòria Pamplona, Reinald Portero Otín, Manuel |
Keywords: | Esclerosi lateral amiotròfica RNA Amyotrophic lateral sclerosis RNA |
Issue Date: | 1-Aug-2022 |
Publisher: | The Company of Biologists |
Abstract: | To evaluate senescence mechanisms, including senescence-associated secretory phenotype (SASP), in the motor neuron disease model hSOD1-G93A, we quantified the expression of p16 and p21 and senescence-associated Ji-galactosidase (SA-Ji-gal) in nervous tissue. As SASP markers, we measured the mRNA levels of Il1a , Il6 , Ifna and Ifnb. Furthermore, we explored whether an alteration of alternative splicing is associated with senescence by measuring the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR DNA-binding protein (TDP-43; encoded by Tardbp). Transgenic mice showed an atypical senescence profile with high p16 and p21 mRNA and protein in glia, without the canonical increase in SA-Ji-gal activity. Consistent with SASP, there was an increase in Il1a and Il6 expression, associated with increased TNF-R and M-CSF protein levels, with females being partially protected. TDP-43 splicing activity was compromised in this model, and the senolytic drug Navitoclax did not alter the disease progression. This lack of effect was reproduced in vitro , in contrast to dasatinib and quercetin, which diminished p16 and p21. Our findings show a non-canonical profile of senescence biomarkers in the model hSOD1-G93A. |
Note: | Reproducció del document publicat a: https://doi.org/10.1242/dmm.049059 |
It is part of: | Disease Models & Mechanisms, 2022, vol. 15, núm. 8 |
URI: | http://hdl.handle.net/2445/190166 |
Related resource: | https://doi.org/10.1242/dmm.049059 |
ISSN: | 1754-8411 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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