A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers

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 lev...

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Detalles Bibliográficos
Autores: 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-Otin, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/190166
Acceso en línea:https://hdl.handle.net/2445/190166
Access Level:acceso abierto
Palabra clave:Esclerosi lateral amiotròfica
RNA
Amyotrophic lateral sclerosis
Descripción
Sumario: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.

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