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Published on: May 15, 2019
The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
Xuexin Li1, Ivó Hernandez2, Seda Koyuncu3
1Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden.
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.
Insights
The anti-leprosy drug clofazimine shows promise for treating polyglutamine (PolyQ) diseases. This drug effectively reduced toxicity in cellular and animal models, offering a potential new therapeutic avenue.
Area of Science:
- Neurodegenerative diseases
- Genetics
- Drug discovery
Background:
- PolyQ diseases are fatal, autosomal dominant neurodegenerative disorders.
- Current treatments for PolyQ diseases are ineffective.
Purpose of the Study:
- Identify drugs to reduce toxicity of mutant huntingtin protein.
- Investigate clofazimine's therapeutic potential for PolyQ diseases.
Main Methods:
- High-throughput chemical screen for toxicity-reducing compounds.
- In vitro and in vivo testing in polyglutamine toxicity models.
- Analysis of transcriptional signatures and mitochondrial biogenesis.
Main Results:
- Clofazimine identified as a hit, reducing polyQ toxicity in vitro.
- Clofazimine stimulates mitochondrial biogenesis via PPARγ activation.
- Clofazimine demonstrated efficacy in zebrafish and worm models of PolyQ disease.
Conclusions:
- Repurposing clofazimine is a potential treatment strategy for PolyQ diseases.
- Clofazimine's mechanism involves enhancing mitochondrial function.
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