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

Animals Corpus Striatum / drug effects DNA / metabolism DNA Mismatch Repair / drug effects DNA Replication / drug effects Disease Models, Animal Humans Huntingtin Protein / genetics Huntington Disease / drug therapy Male Mice Mice, Transgenic Microsatellite Instability Mutation Naphthyridines / pharmacology Quinolones / pharmacology Ribonucleases / metabolism TATA-Box Binding Protein / genetics Transcription, Genetic Trinucleotide Repeat Expansion / drug effects

Journal

Nature genetics

ISSN: 1546-1718

Titre abrégé: Nat Genet

Pays: United States

ID NLM: 9216904

Informations de publication

Date de publication:
02 2020

Historique:

received: 20 10 2018

accepted: 19 12 2019

pubmed: 16 2 2020

medline: 14 4 2020

entrez: 16 2 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-019-0575-8 PMID: 32060489 PMC: PMC7043212

pubmed: 32060489

doi: 10.1038/s41588-019-0575-8

pii: 10.1038/s41588-019-0575-8

pmc: PMC7043212

mid: NIHMS1547031

doi:

Substances chimiques

HTT protein, human 0

Htt protein, mouse 0

Huntingtin Protein 0

Naphthyridines 0

Quinolones 0

TATA-Box Binding Protein 0

TBP protein, human 0

naphthyridine-azaquinolone 0

DNA 9007-49-2

Ribonucleases EC 3.1.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

146-159

Subventions

Organisme : NIEHS NIH HHS

ID : R01 ES014737

Pays : United States

Organisme : NHGRI NIH HHS

ID : R01 HG010169

Pays : United States

Organisme : CIHR

ID : FRN388879

Pays : Canada

Organisme : CIHR

ID : FRN148910

Pays : Canada

Commentaires et corrections

Type : CommentIn

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