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

Autor:	Li X; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden., Hernandez I; Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain., Koyuncu S; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany., Kis B; HCEMM-SU, Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary; Institute of Translational Medicine, Semmelweis University, Budapest, Hungary., Häggblad M; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden., Lidemalm L; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden., Abbas AA; HCEMM-SU, Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary; Institute of Translational Medicine, Semmelweis University, Budapest, Hungary., Bendegúz S; HCEMM-SU, Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary; Institute of Translational Medicine, Semmelweis University, Budapest, Hungary., Göblös A; Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, H-6720, Szeged, Hungary., Brautigam L; Zebrafish Core Facility, Karolinska Institute, S-171 21, Stockholm, Sweden., Lucas JJ; Center for Molecular Biology, 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid, 28049, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Carreras-Puigvert J; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden., Hühn D; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden., Pircs K; HCEMM-SU, Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary; Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Lund, Sweden., Vilchez D; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany., Fernandez-Capetillo O; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden; Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain. Electronic address: oscar.fernandez-capetillo@ki.se.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 May; Vol. 103, pp. 105124. Date of Electronic Publication: 2024 May 02.
DOI:	10.1016/j.ebiom.2024.105124
Abstrakt:	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 94 ). 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 94 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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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