Rett syndrome (RTT) is a debilitating neurodevelopmental disorder primarily affecting females. Although it is clear that mutations in a single gene (MECP2) cause the disease, the precise mechanism underlying the pathologies is not well understood. Natural history studies of RTT patients and research using mouse models of RTT and RTT patient iPSC models have all contributed to our current understanding of the disease. Because each experimental platform has its unique strength and limitations, before insights gained on a particular platform become useful for therapy development, it is critical to validate the findings on multiple platforms acros disciplines. Recently, a suppressor screen in a RTT mouse model has identified altered cholesterol metabolism as a likely influence on disease progression, opening the door to potential intervention, since many key players in the pathway are drug targets in other unrelated diseases. However, the mouse study did not identify the cellular origin of the altered cholesterol metabolism in the brain. Two subsequent studies further demonstrated some impairment in cholesterol metabolism in the plasma and fibroblasts from RTT patients. Yet, the significance of these studies is limited because plasma cholesterol levels are not correlated with brain cholesterol homeostasis and fibroblasts are notoriously poor models of brain cells, hence leaving unanswered the question of a potential contribution of abnormal cholesterol metabolism to the pathogenesis of Rett syndrome, a widely recognized neurobiological condition. Also unanswered with these two studies is the question of a correlation between the observed cholesterol abnormalities and the RTT clinical phenotype or disease progression. To begin addressing these unanswered questions, we propose to 1) determine whether sterol metabolism is altered in astrocytes differentiated from mutant RTT induced pluripotent stem cells (iPSCs) and whether manipulation of the cholesterol synthesis pathway may rescue the cellular phenotypes in RTT astrocytes; and 2) perform a refined exploration of sterol metabolism in RTT patients facilitating future correlations between sterol biomarkers and clinical phenotypes. Results from our proposed study will help to determine whether sterol metabolism is altered in RTT patients or brain cells derived from these patients (as suggested by findings in RTT mouse models), and reveal the significance of such alteration in the context of other clinical symptoms. If successful, our study will not only advance our understanding of RTT disease mechanisms, but also lead to potential treatments for RTT patients.
Sterol Metabolism in Rett Syndrome Project Narrative Rett syndrome (RTT) is a debilitating neurodevelopmental disorder predominantly affecting females. Although the genetic cause of the disease has been identified as mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene, the disease mechanism is not well understood. This study will explore the potential role of sterol metabolism in RTT pathogenesis, which may advance our understanding of the disease mechanism and help developing treatments.
| Steyer, Benjamin; Bu, Qian; Cory, Evan et al. (2018) Scarless Genome Editing of Human Pluripotent Stem Cells via Transient Puromycin Selection. Stem Cell Reports 10:642-654 |
