Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease

Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleosid...

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Autores: Brokate Llanos, Ana María, Sanchez-Ibañez, Mireya, Pérez-Jiménez, Mercedes M., Monje, José Manuel, Gómez-Marín, Carlos, Caro, Carlos, Vivar-Rios, Carlos, Moreno Mateos, Miguel A., García-Martín, Maria L., Muñoz Ruiz, Manuel Jesús, Royo, Jose L.
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad Pablo de Olavide (UPO)
Repositorio:RIO. Repositorio Institucional Olavide
Idioma:inglés
OAI Identifier:oai:rio.upo.es:10433/23790
Acceso en línea:https://hdl.handle.net/10433/23790
Access Level:acceso abierto
Palabra clave:Alzheimer
Caenorhabditis elegans
RRM2B
Gemcitabine
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spelling Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s diseaseBrokate Llanos, Ana MaríaSanchez-Ibañez, MireyaPérez-Jiménez, Mercedes M.Monje, José ManuelGómez-Marín, CarlosCaro, CarlosVivar-Rios, CarlosMoreno Mateos, Miguel A.García-Martín, Maria L.Muñoz Ruiz, Manuel JesúsRoyo, Jose L.AlzheimerCaenorhabditis elegansRRM2BGemcitabineAlzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2′, 2′-difluoro 2′deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment.Oxford Academic20252025-04-1620242024-02-2720242024-02-27journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10433/23790reponame:RIO. Repositorio Institucional Olavideinstname:Universidad Pablo de Olavide (UPO)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:rio.upo.es:10433/237902026-06-13T12:46:27Z
dc.title.none.fl_str_mv Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
title Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
spellingShingle Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
Brokate Llanos, Ana María
Alzheimer
Caenorhabditis elegans
RRM2B
Gemcitabine
title_short Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
title_full Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
title_fullStr Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
title_full_unstemmed Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
title_sort Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer’s disease
dc.creator.none.fl_str_mv Brokate Llanos, Ana María
Sanchez-Ibañez, Mireya
Pérez-Jiménez, Mercedes M.
Monje, José Manuel
Gómez-Marín, Carlos
Caro, Carlos
Vivar-Rios, Carlos
Moreno Mateos, Miguel A.
García-Martín, Maria L.
Muñoz Ruiz, Manuel Jesús
Royo, Jose L.
author Brokate Llanos, Ana María
author_facet Brokate Llanos, Ana María
Sanchez-Ibañez, Mireya
Pérez-Jiménez, Mercedes M.
Monje, José Manuel
Gómez-Marín, Carlos
Caro, Carlos
Vivar-Rios, Carlos
Moreno Mateos, Miguel A.
García-Martín, Maria L.
Muñoz Ruiz, Manuel Jesús
Royo, Jose L.
author_role author
author2 Sanchez-Ibañez, Mireya
Pérez-Jiménez, Mercedes M.
Monje, José Manuel
Gómez-Marín, Carlos
Caro, Carlos
Vivar-Rios, Carlos
Moreno Mateos, Miguel A.
García-Martín, Maria L.
Muñoz Ruiz, Manuel Jesús
Royo, Jose L.
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Alzheimer
Caenorhabditis elegans
RRM2B
Gemcitabine
topic Alzheimer
Caenorhabditis elegans
RRM2B
Gemcitabine
description Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2′, 2′-difluoro 2′deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aβ1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-02-27
2024
2024-02-27
2025
2025-04-16
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10433/23790
url https://hdl.handle.net/10433/23790
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford Academic
publisher.none.fl_str_mv Oxford Academic
dc.source.none.fl_str_mv reponame:RIO. Repositorio Institucional Olavide
instname:Universidad Pablo de Olavide (UPO)
instname_str Universidad Pablo de Olavide (UPO)
reponame_str RIO. Repositorio Institucional Olavide
collection RIO. Repositorio Institucional Olavide
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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