The Chinese University of Hong Kong (CUHK), Hong Kong
Abstract: Pathogenic variants in the CDKL5 genes result in CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental disorder. Patients with CDD exhibit a wide range of symptoms, including early-onset epilepsy, global developmental delay, intellectual disability, autistic features, visual impairment, and motor impairment. The CDKL5 gene is located at position 22 on the X chromosome and encodes the CDKL5 protein, a member of the serine/threonine kinase family. Currently, the molecular mechanisms underlying the pathophysiology of CDD remain unclear and there is no cure for patients with CDD. Notably, genetic knockout of CDKL5 in mice fails to reproduce the seizure phenotypes observed in human patients, emphasizing the urgent need for disease-relevant human models of CDD to elucidate the functional roles of CDKL5. To comprehensively study the molecular functions of CDKL5 and expedite therapeutic development, it is crucial to identify its direct substrates and dissect its function in clinically relevant cell types and models. Three-dimensional brain organoids generated from patient-derived induced pluripotent stem cells (iPSCs) serve as a robust model for investigating the underlying mechanisms of CDD with a human background. By employing single-cell RNA sequencing and immunostaining techniques, this study uncovered previously unrecognized proliferation deficits among major neural progenitor stem cells in CDD organoids. Given that CDKL5 is a serine/threonine kinase, the study explored several potential downstream substrates, including the microtubule-binding protein EB2. The findings of this study propose a novel mechanism underlying CDD pathology and offer crucial insights into the exploration of novel treatment strategies for CDD.
Funding Source: Lo Kwee-Seong Biomedical Research Fund (J.I), Faculty Innovation Award (FIA2020/A/04) from the Faculty of Medicine, CUHK (J.I.), Hong Kong RGC Research Matching Grant Scheme (J.I.) and Hong Kong PhD Fellowship (PF20-43681; Y.Z.).
