INDYCSB

There is currently no established treatment for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging and death in childhood. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome. We identified the gene Helicase 89B (Hel89B) 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, rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional resolution of non-B DNA. Notably, this appears to be a common effect of a ketogenic diet. Examination of transcriptome in cerebella of WT, INDY, CSB and DKO mice, fed standard diet (SD) or ketogenic diet (KD).