Aripiprazole offsets mutant ATXN3-induced motor dysfunction by targeting dopamine D2 and serotonin 1A and 2A receptors in C. elegans

Detalhes bibliográficos
Autor(a) principal: Jalles, Ana
Data de Publicação: 2022
Outros Autores: 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
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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spelling 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
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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
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