The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ

Background: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies. Methods: A high-throughput chemical screen was conducted to identify drugs that lower the...

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Autores: Li, Xuexin, Hernandez, Ivó, Koyuncu, Seda, Kis, Balázs, Häggblad, Maria, Lidemalm, Louise, Abbas, Anna A., Bendegúz, Sramkó, Göblös, Anikó, Brautigam, Lars, Lucas, Jose J., Carreras-Puigvert, Jordi, Hühn, Daniela, Pircs, Karolina, Vilchez, David, Fernandez-Capetillo, Oscar
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2024
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/366880
Acesso em linha:http://hdl.handle.net/10261/366880
Access Level:Acceso aberto
Palavra-chave:polyQ
Huntington's disease
Chemical screening
PPARγ
Mitochondria
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spelling The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγLi, XuexinHernandez, IvóKoyuncu, SedaKis, BalázsHäggblad, MariaLidemalm, LouiseAbbas, Anna A.Bendegúz, SramkóGöblös, AnikóBrautigam, LarsLucas, Jose J.Carreras-Puigvert, JordiHühn, DanielaPircs, KarolinaVilchez, DavidFernandez-Capetillo, OscarpolyQHuntington's diseaseChemical screeningPPARγMitochondriaBackground: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies. Methods: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington's disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity. Findings: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease. Interpretation: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases. Funding: A full list of funding sources can be found in the acknowledgments section.We thank the Chemical Biology Consortium Sweden for their help with the chemical libraries. Research was funded by grants from the Cancerfonden foundation (CAN 21/1529) and the Swedish Research Council (VR) (538-2014-31) to OF; and the Spanish Ministry of Science and Innovation and Spanish Ministry of Science (PID2021-123141OBI00 MCIU/AEI/FEDER, UE) to JJL, and the ICGEB CRP/HUN21-05_EC and the TKP-NVA-20 to KP. None of the funders contributed to the design, analysis or reporting of this study.Swedish Research CouncilMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/366880reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-123141OB-I00http://dx.doi.org/10.1016/j.ebiom.2024.105124Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3668802026-05-22T06:33:51Z
dc.title.none.fl_str_mv The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
title The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
spellingShingle The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
Li, Xuexin
polyQ
Huntington's disease
Chemical screening
PPARγ
Mitochondria
title_short The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
title_full The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
title_fullStr The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
title_full_unstemmed The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
title_sort The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
dc.creator.none.fl_str_mv Li, Xuexin
Hernandez, Ivó
Koyuncu, Seda
Kis, Balázs
Häggblad, Maria
Lidemalm, Louise
Abbas, Anna A.
Bendegúz, Sramkó
Göblös, Anikó
Brautigam, Lars
Lucas, Jose J.
Carreras-Puigvert, Jordi
Hühn, Daniela
Pircs, Karolina
Vilchez, David
Fernandez-Capetillo, Oscar
author Li, Xuexin
author_facet Li, Xuexin
Hernandez, Ivó
Koyuncu, Seda
Kis, Balázs
Häggblad, Maria
Lidemalm, Louise
Abbas, Anna A.
Bendegúz, Sramkó
Göblös, Anikó
Brautigam, Lars
Lucas, Jose J.
Carreras-Puigvert, Jordi
Hühn, Daniela
Pircs, Karolina
Vilchez, David
Fernandez-Capetillo, Oscar
author_role author
author2 Hernandez, Ivó
Koyuncu, Seda
Kis, Balázs
Häggblad, Maria
Lidemalm, Louise
Abbas, Anna A.
Bendegúz, Sramkó
Göblös, Anikó
Brautigam, Lars
Lucas, Jose J.
Carreras-Puigvert, Jordi
Hühn, Daniela
Pircs, Karolina
Vilchez, David
Fernandez-Capetillo, Oscar
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Swedish Research Council
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv polyQ
Huntington's disease
Chemical screening
PPARγ
Mitochondria
topic polyQ
Huntington's disease
Chemical screening
PPARγ
Mitochondria
description Background: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies. Methods: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington's disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity. Findings: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease. Interpretation: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases. Funding: A full list of funding sources can be found in the acknowledgments section.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/366880
url http://hdl.handle.net/10261/366880
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-123141OB-I00
http://dx.doi.org/10.1016/j.ebiom.2024.105124
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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