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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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:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.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
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spelling A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkersTorres Cabestany, PascualAnerillas Aljama, CarlosRamírez-Núñez, OmarEncinas Martín, MarioPovedano, MònicaAndrés Benito, Pol Ferrer, IsidreAyala Jové, Ma. Victoria (Maria Victoria)Pamplona Gras, ReinaldPortero Otín, ManuelAmyotrophic lateral sclerosisNavitoclaxSenolyticNeuroinflammationTherapyCell cycleCryptic exonTo 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.Grants supporting this work were received from the Instituto de Salud Carlos III (PI 17-00134, PI 20-0155) to M.P.-O., Generalitat de Catalunya (2017SGR696) to R.P., and Ministerio de Ciencia, Innovación y Universidades (BFU2017-83646-P, AEI, FEDER, UE) to M.E. P.T. is a ‘Margarita Salas’ fellow from the Spanish Ministry of Universities (financed by European Commission-Next Generation EU funds). Support was also received from Fundación Españ ola Investigación Esclerosis Lateral (FUNDELA), RedELA-Plataforma Investigación and FundacióMiquel Valls (Jack Van den Hoek donation). European Regional Development Fund (FEDER) funds are acknowledged (‘A way to make Europe’). These funding bodies had no roles in the design of the study and collection, analysis and interpretation of data, or writing of the manuscript. Open Access funding provided by Universitat de Lleida. Deposited in PMC for immediate release.The Company of Biologists2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1242/dmm.049059http://hdl.handle.net/10459.1/84466reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a https://doi.org/10.1242/dmm.049059Disease Models & Mechanisms, 2022, vol. 15, núm. 8, art. 049059.cc-by (c) Pascual Torres Cabestany et al., 2022info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/844662026-06-24T12:42:17Z
dc.title.none.fl_str_mv A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
title A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
spellingShingle A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
Torres Cabestany, Pascual
Amyotrophic lateral sclerosis
Navitoclax
Senolytic
Neuroinflammation
Therapy
Cell cycle
Cryptic exon
title_short A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
title_full A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
title_fullStr A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
title_full_unstemmed A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
title_sort A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers
dc.creator.none.fl_str_mv 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
author Torres Cabestany, Pascual
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Amyotrophic lateral sclerosis
Navitoclax
Senolytic
Neuroinflammation
Therapy
Cell cycle
Cryptic exon
topic Amyotrophic lateral sclerosis
Navitoclax
Senolytic
Neuroinflammation
Therapy
Cell cycle
Cryptic exon
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1242/dmm.049059
http://hdl.handle.net/10459.1/84466
url https://doi.org/10.1242/dmm.049059
http://hdl.handle.net/10459.1/84466
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.1242/dmm.049059
Disease Models & Mechanisms, 2022, vol. 15, núm. 8, art. 049059.
dc.rights.none.fl_str_mv cc-by (c) Pascual Torres Cabestany et al., 2022
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c) Pascual Torres Cabestany et al., 2022
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv The Company of Biologists
publisher.none.fl_str_mv The Company of Biologists
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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