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 β-galactosidase (SA-β-gal) in nervous tissue. As SASP markers, we measured the mRNA level...

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Detalles Bibliográficos
Autores: Torres Cabestany, Pascual, Anerillas Aljama, Carlos, Ramírez-Núñez, Omar, Encinas Martín, Mario, Povedano, Mònica, Andrés Benito, Pol, Ferrer, Isidre, Ayala Jové, Ma. Victoria (Maria Victoria), Pamplona Gras, Reinald, Portero Otín, 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:10459.1/84466
Acceso en línea:https://doi.org/10.1242/dmm.049059
http://hdl.handle.net/10459.1/84466
Access Level:acceso abierto
Palabra clave:Amyotrophic lateral sclerosis
Navitoclax
Senolytic
Neuroinflammation
Therapy
Cell cycle
Cryptic exon
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 β-galactosidase (SA-β-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-β-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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