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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2021)

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.

    Cover page: Understanding the Mechanisms of Stress Related Pathways in Rett Syndrome
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2018)
    To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder.
      Cover page: Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence
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