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The anti-leprosy dr...
The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
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- Li, Xuexin (author)
- Karolinska Institute
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- Hernandez, Ivó (author)
- Spanish National Cancer Research Center (CNIO)
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- Koyuncu, Seda (author)
- University Hospital of Cologne
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- Kis, Balázs (author)
- Semmelweis University
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- Häggblad, Maria (author)
- Karolinska Institutet,Karolinska Institute
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- Lidemalm, Louise (author)
- Karolinska Institutet,Karolinska Institute
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- Abbas, Anna A. (author)
- Semmelweis University
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- Bendegúz, Sramkó (author)
- Semmelweis University
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- Göblös, Anikó (author)
- University of Szeged
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- Brautigam, Lars (author)
- Karolinska Institute
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- Lucas, Jose J. (author)
- CIBER Enfermedades Neurodegenerativas (CIBERNED),Autonomous University of Madrid
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- Carreras-Puigvert, Jordi (author)
- Karolinska Institute
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- Hühn, Daniela (author)
- Karolinska Institutet,Karolinska Institute
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- Pircs, Karolina (author)
- Lund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,LU profilområde: Proaktivt åldrande,Lunds universitets profilområden,Molecular Neurogenetics,Lund University Research Groups,LU Profile Area: Proactive Ageing,Lund University Profile areas,Semmelweis University
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- Vilchez, David (author)
- University Hospital of Cologne
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- Fernandez-Capetillo, Oscar (author)
- Karolinska Institute,Spanish National Cancer Research Center (CNIO)
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(creator_code:org_t)
- 2024
- 2024
- English.
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In: EBioMedicine. - 2352-3964. ; 103
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Abstract
Subject headings
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- 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-Q94). 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-Q94 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- Chemical screening
- Huntington's disease
- Mitochondria
- polyQ
- PPARγ
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Li, Xuexin
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Hernandez, Ivó
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Koyuncu, Seda
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Kis, Balázs
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Häggblad, Maria
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Lidemalm, Louise
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show more...
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Abbas, Anna A.
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Bendegúz, Sramkó
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Göblös, Anikó
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Brautigam, Lars
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Lucas, Jose J.
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Carreras-Puigver ...
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Hühn, Daniela
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Pircs, Karolina
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Vilchez, David
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Fernandez-Capeti ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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EBioMedicine
- By the university
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Lund University
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Karolinska Institutet