Journal
NATURE GENETICS
Volume 52, Issue 2, Pages 146-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-019-0575-8
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Funding
- Canadian Institutes of Health Research [FRN388879, FRN148910]
- Natural Sciences and Engineering Research Council [RGPIN-2016-08355]
- Muscular Dystrophy Canada
- Petroff Family Fund
- Kazman Family Fund
- Marigold Foundation
- National Center of Neurology and Psychiatry [29-4]
- JSPS KAKENHI [24890110, 25713034, 16H05321, 26000007]
- Cancer Research UK Catalyst Award [C569/A24991]
- US National Institutes of Health [2 R01 ES014737]
- US National Institutes of Health (NIH) [HG010169]
- Fonds de Recherche de Sante Quebec Chair in Genome Stability
- TCAG (SickKids)
- Grants-in-Aid for Scientific Research [16H05321, 25713034, 24890110] Funding Source: KAKEN
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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 MutS beta. 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.
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