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

Abstract

SUMMARYPolyQ 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. Here, we present our results from a High-Throughput chemical screen oriented to find drugs that lower the toxicity of a protein containing the first exon from the Huntington’s disease protein huntingtin (HTT) harboring 94 glutamines (Htt-Q94). Our screening identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models as well as in a zebrafish model of polyQ toxicity. Computational analyses of transcriptional signatures, together with molecular modeling and biochemical assays revealed that clofazimine is an agonist of the peroxisome proliferator activated receptor gamma (PPARγ), previously suggested as a potential therapy for HD by stimulating mitochondrial biogenesis. Accordingly, clofazimine rescued the mitochondrial dysfunction triggered by Htt-Q94expression. Together, our results support the potential of clofazimine repurposing for the treatment of PolyQ diseases.