Metabolic regulation by the MeCP2/HDAC3 transcriptional corepressor complex points to new therapeutic targets in Rett syndrome. S. M. Kyle1,2, C. M. Buchovecky1, M. J. Justice2 1) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario.
Metabolic dysregulation can lead to downstream pathogenesis in nearly all tissues and organ systems. In recent decades, a large body of data has implicated metabolic perturbations in neurological development and degeneration. In particular, dysregulation of cholesterol trafficking and biosynthesis are responsible for the onset of Neimann-Pick type C and Smith-Lemli Opitz syndrome, respectively. Furthermore, Fragile X syndrome, Alzheimer, Parkinson, and Huntington diseases have all been linked to aberrant cholesterol homeostasis. Rett syndrome (RTT) is a progressive neurodevelopmental disorder of females primarily caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant random mutagenesis suppressor screen in Mecp2 null mice. One suppressor identifies a stop codon mutation in a rate-limiting enzyme in cholesterol biosynthesis, which ameliorates RTT-like symptoms and increases longevity in Mecp2 null mice by altering brain cholesterol homeostasis. Although RTT has been classically labeled a neurological disorder, these studies suggest that a metabolic component contributes to pathology. Here we show that the Mecp2 mutation induces metabolic defects in mice including fatty liver, increased lipolysis, and insulin resistance in muscle and adipose. These metabolic phenotypes are strikingly similar to that in mice with a liver-specific knockout of histone deacetylase 3 (Hdac3), a potent regulator of lipogenesis and cholesterol biosynthesis. Consistently, we show that MeCP2 and HDAC3 work in a complex to suppress expression of the rate-limiting cholesterol enzyme identified in our screen. Our data suggest a novel metabolic component present in RTT arising from loss of interaction between MeCP2 and HDAC3. These studies inform highly targetable therapeutic pathways relevant to treating RTT; remarkably, statin drug administration improves motor symptoms and confers increased longevity in Mecp2 null mice. The suppressor mutation also suggests that symptoms may be modified in patients by mutations in genes that affect metabolism. In support of this idea, a subset of RTT patients has increased serum cholesterol and triglycerides, independent of body mass index. Our ongoing studies point to additional metabolic pathways that are prime targets in the pursuit of preventing morbidities associated with Rett syndrome.
You may contact the first author (during and after the meeting) at