One drug， two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV， TAT-BIND reduces cell death， formation of GGGGCC RNA foci， and levels of poly-GR， poly-GA， and poly-GP dipeptide proteins in cell m... More
One drug， two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV， TAT-BIND reduces cell death， formation of GGGGCC RNA foci， and levels of poly-GR， poly-GA， and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein， restores rRNA maturation， and inhibits mislocalization of nucleolin and B23， which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD， TAT-BIND suppresses retinal degeneration， rescues climbing ability， and extends the lifespan of flies. In contrast， TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)-expressing flies， which generate only poly-GR protein toxicity， indicating BIND ameliorates toxicity in C9ALS-FTD models via a (GGGGCC)-dependent inhibitory mechanism. Our findings demonstrated that， apart from being a potential therapeutic for polyQ diseases， BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration， highlighting its potential application in C9ALS-FTD treatment.
