Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/78471 |
Resumo: | The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D<sub>2</sub>-like and serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole. |
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Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans5-HT (5-hydroxytryptamine; serotonin)DopamineMachado-Joseph diseaseSpinocerebellar ataxia type 3AntipsychoticsTherapy5-HT (5-hydroxytryptamineserotonin)Science & TechnologyThe atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D<sub>2</sub>-like and serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.This work was funded by FEDER through the Competitiveness Internationalization Operational Program (POCI) and by National funds through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-0 31987, NORTE-01-0145-FEDER-000013, and NORTE-01-0145-FEDER-000023, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement through the European Regional Development Fund (ERDF) and by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020). Additionally, this project was supported by the National Ataxia Foundation (NAF). A.J., J.P.-S., D.V.-C., and J.D.S. were supported by the FCT individual fellowships SFRH/BD/76613/2011, PD/BDE/127834/2016, SFRH/BD/147826/2019, and PD/BD/128074/2016, respectively.Multidisciplinary Digital Publishing Institute (MDPI)Universidade do MinhoJalles, AnaVieira, Cármen Maria LealPereira-Sousa, JoanaCampos, Daniela VilasboasMota, Ana FranciscaVasconcelos, SaraLomba, Bruna Melissa FerreiraCosta, Marta Daniela AraújoSilva, Jorge Diogo daMaciel, P.Castro, Andreia Cristiana Teixeira2022-02-032022-02-03T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/78471engJalles, A.; Vieira, C.; Pereira-Sousa, J.; Vilasboas-Campos, D.; Mota, A.F.; Vasconcelos, S.; Ferreira-Lomba, B.; Costa, M.D.; Da Silva, J.D.; Maciel, P.; Teixeira-Castro, A. Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans. Biomedicines 2022, 10, 370. https://doi.org/10.3390/biomedicines100203702227-905910.3390/biomedicines10020370370https://www.mdpi.com/2227-9059/10/2/370info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:04:03Zoai:repositorium.sdum.uminho.pt:1822/78471Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:54:14.992415Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
title |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
spellingShingle |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans Jalles, Ana 5-HT (5-hydroxytryptamine; serotonin) Dopamine Machado-Joseph disease Spinocerebellar ataxia type 3 Antipsychotics Therapy 5-HT (5-hydroxytryptamine serotonin) Science & Technology |
title_short |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
title_full |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
title_fullStr |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
title_full_unstemmed |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
title_sort |
Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans |
author |
Jalles, Ana |
author_facet |
Jalles, Ana Vieira, Cármen Maria Leal Pereira-Sousa, Joana Campos, Daniela Vilasboas Mota, Ana Francisca Vasconcelos, Sara Lomba, Bruna Melissa Ferreira Costa, Marta Daniela Araújo Silva, Jorge Diogo da Maciel, P. Castro, Andreia Cristiana Teixeira |
author_role |
author |
author2 |
Vieira, Cármen Maria Leal Pereira-Sousa, Joana Campos, Daniela Vilasboas Mota, Ana Francisca Vasconcelos, Sara Lomba, Bruna Melissa Ferreira Costa, Marta Daniela Araújo Silva, Jorge Diogo da Maciel, P. Castro, Andreia Cristiana Teixeira |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Jalles, Ana Vieira, Cármen Maria Leal Pereira-Sousa, Joana Campos, Daniela Vilasboas Mota, Ana Francisca Vasconcelos, Sara Lomba, Bruna Melissa Ferreira Costa, Marta Daniela Araújo Silva, Jorge Diogo da Maciel, P. Castro, Andreia Cristiana Teixeira |
dc.subject.por.fl_str_mv |
5-HT (5-hydroxytryptamine; serotonin) Dopamine Machado-Joseph disease Spinocerebellar ataxia type 3 Antipsychotics Therapy 5-HT (5-hydroxytryptamine serotonin) Science & Technology |
topic |
5-HT (5-hydroxytryptamine; serotonin) Dopamine Machado-Joseph disease Spinocerebellar ataxia type 3 Antipsychotics Therapy 5-HT (5-hydroxytryptamine serotonin) Science & Technology |
description |
The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D<sub>2</sub>-like and serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-02-03 2022-02-03T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/78471 |
url |
https://hdl.handle.net/1822/78471 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Jalles, A.; Vieira, C.; Pereira-Sousa, J.; Vilasboas-Campos, D.; Mota, A.F.; Vasconcelos, S.; Ferreira-Lomba, B.; Costa, M.D.; Da Silva, J.D.; Maciel, P.; Teixeira-Castro, A. Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans. Biomedicines 2022, 10, 370. https://doi.org/10.3390/biomedicines10020370 2227-9059 10.3390/biomedicines10020370 370 https://www.mdpi.com/2227-9059/10/2/370 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799132324736008192 |