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

Li, Xuexin ; Hernandez, Ivó ; Koyuncu, Seda ; Kis, Balázs ; Häggblad, Maria ; Lidemalm, Louise ; Abbas, Anna A. ; Bendegúz, Sramkó ; Göblös, Anikó and Brautigam, Lars , et al. (2024) In EBioMedicine 103.
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Chemical screening, Huntington's disease, Mitochondria, polyQ, PPARγ
in
EBioMedicine
volume
103
article number
105124
publisher
Elsevier
external identifiers
  • pmid:38701619
  • scopus:85191984620
ISSN
2352-3964
DOI
10.1016/j.ebiom.2024.105124
language
English
LU publication?
yes
id
08238615-1985-451b-9ed1-992c6dc002a9
date added to LUP
2024-05-14 13:22:29
date last changed
2024-06-11 16:06:01
@article{08238615-1985-451b-9ed1-992c6dc002a9,
  abstract     = {{<p>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<sub>94</sub>). 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<sub>94</sub> 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.</p>}},
  author       = {{Li, Xuexin and Hernandez, Ivó and Koyuncu, Seda and Kis, Balázs and Häggblad, Maria and Lidemalm, Louise and Abbas, Anna A. and Bendegúz, Sramkó and Göblös, Anikó and Brautigam, Lars and Lucas, Jose J. and Carreras-Puigvert, Jordi and Hühn, Daniela and Pircs, Karolina and Vilchez, David and Fernandez-Capetillo, Oscar}},
  issn         = {{2352-3964}},
  keywords     = {{Chemical screening; Huntington's disease; Mitochondria; polyQ; PPARγ}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2024.105124}},
  doi          = {{10.1016/j.ebiom.2024.105124}},
  volume       = {{103}},
  year         = {{2024}},
}