UCLA

Rett syndrome is a severe neurodevelopmental disorder that arises due to a mutation inmethyl-CpG-binding protein 2 (MECP2). Rett syndrome patients suffer delay in mental, physical and cognitive development. The mechanism underlying the onset of Rett syndrome remains poorly understood. We used Rett patient derived human induced pluripotent stem cells (hiPSCs) to model Rett syndrome in vitro in an attempt to elucidate the pathways implicated in Rett phenotype. We discovered that Rett neurons undergo neuronal stress resulting in an increased expression of OCT1 and P53 target genes. In addition, mutant neurons exhibit premature senescence accompanied by elevated levels of DNA damage. Analyzing neuronal phenotype revealed a significant decrease in the complexity of dendritic arborization. This led us to explore these neuronal stress signatures further by analyzing Rett patient brain samples with single-cell RNA sequencing. We discovered that lack of MECP2 leads to misregulated synaptic genes as iii well as abnormal metabolism. We confirmed faulty metabolism and mitochondrial respiration in our in vitro model, and showed that various types of neuronal stress lead to induction of OCT1 in vitro.