Journal Article

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo

Li, Jinxing, Chiang, Karen, Edward, Lisa-Monique, Murata, Asako, Joshi, Niraj, Wang, Xiaoxiao, Lanni, Stella, Caron, Marie-Christine, Davidson, Scott, Huddleston, John, Layeghifard, Mehdi, Tanaka, Hana, Otabe, Takahiro, Panigrahi, Gagan B., Lee, Marietta Y. W. T., Hayakawa, Hideki, Santibanez-Koref, Mauro, Munson, Katherine M., Gallon, Richard, Mochizuki, Hideki, Prasolava, Tanya, Pearson, Christopher E., Masson, Jean-Yves, Eichler, Evan E., Wold, Marc S., Nakamori, Masayuki, Luo, Jennifer, Shlien, Adam, Sakata, Akihiro, Takahashi, Masanori P., Gall-Duncan, Terence, Nakatani, Kazuhiko

2020

Overview

In many repeat diseases, such as Huntington’s disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSβ. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats. Naphthyridine-azaquinolone specifically binds slipped-CAG DNA intermediates, induces contractions of expanded repeats and reduces mutant HTT protein aggregates in cell and animal models of Huntington’s disease.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/106 / 14/1 / 14/63 / 38/22 / 38/23 / 38/77 / 45/43 / 631/154/1435 / 631/208/200 / 64/60 / 82 / Age / Agriculture / Animal Genetics and Genomics / Animals / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Corpus Striatum - drug effects / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA - metabolism / DNA biosynthesis / DNA Mismatch Repair - drug effects / DNA repair / DNA replication / DNA Replication - drug effects / DNA structure / Gene Function / Genetic transcription / High-definition television / Human Genetics / Humans / Huntingtin Protein - genetics / Huntingtin Protein - metabolism / Huntington Disease - drug therapy / Huntington Disease - genetics / Huntington Disease - pathology / Huntington's disease / Huntingtons disease / Hybridization / Intermediates / Male / Mice / Mice, Transgenic / Microsatellite Instability / Mutants / Mutation / Naphthyridines - pharmacology / Neostriatum / Pathogenesis / Polyglutamine / Proteins / Quinolones - pharmacology / Ribonucleases - metabolism / Spiny neurons / TATA-Box Binding Protein - genetics / Transcription / Transcription, Genetic / Trinucleotide Repeat Expansion - drug effects / Trinucleotide repeats