Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2018)

Cyclin-dependent kinase-like 5 (CDKL5) syndrome is a neurodevelopmental disorder that results in early-onset intractable seizures, mental retardation, and a host of autistic phenotypes. Although the role of CDKL5 is not well understood, previous studies have implicated it plays a crucial role within the AKT/mTOR pathways, which regulate cellular proliferation, apoptosis, and synaptogenesis. This study focused on generating neural progenitor cells (NPCs) and subsequently differentiating them into neurons, for the purpose of modeling the effects of CDKL5 mutations on the phenotypes listed above. hiPSC-derived CDKL5 NPCs exhibited decreased cell proliferation and increased apoptosis as compared to controls, which is congruent with the findings of previous studies with regards to inactivation of the AKT/mTOR pathways. Furthermore, hiPSC-derived CDKL5 neurons displayed no change in total dendritic length but appeared to grow more slowly during early neurodevelopment as compared to controls. These neurons also had a greater density of dendritic spines, with increased motility, as compared to controls. These findings conflict with the results from previous CDKL5 studies based on mouse knockout models. The discrepancy in results suggests that CDKL5 function may not be preserved across species, a claim that is supported by the fact that the murine models do not recapitulate the defining feature of CDKL5: early-onset intractable seizures.

    Cover page: CDKL5 iPSC-derived Neural Cells Exhibit Deficiencies in Growth and Increased Apoptosis
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients' symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protein were used to generate neural cells. Proteomic and phosphoproteomic approaches revealed disruption of several pathways, including microtubule-based processes and cytoskeleton organization. While CDD-derived neural progenitor cells have proliferation defects, neurons showed morphological alterations and compromised glutamatergic synaptogenesis. Moreover, the electrical activity of CDD cortical neurons revealed hyperexcitability during development, leading to an overly synchronized network. Many parameters of this hyperactive network were rescued by lead compounds selected from a human high-throughput drug screening platform. Our results enlighten cellular, molecular, and neural network mechanisms of genetic epilepsy that could ultimately promote novel therapeutic opportunities for patients.
      Cover page: Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy
      Top