Author:
Petr Michael Angelo,Carmona-Marin Lina M,Tulika Tulika,Kristensen Stella,Reves Simon,Bakula Daniela,Keijzers Guido,Osborne Brenna,Mitchell Sarah J,Hamilton Sam,Kato Jonathan,Alfaras Irene,Teklu Amanuel A.,Heckenbach Indra,Madsen Jakob,Ezra Michael Ben,Mkrtchyan Garik,Varner Erika,Fink Benjamin,Krusenstiern Eliana von,Snyder Nathaniel W,Herranz Hector,Cabo Rafael de,Scheibye-Knudsen Morten
Abstract
SUMMARYThere is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csbm/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.
Publisher
Cold Spring Harbor Laboratory