Novel CDKL5 targets identified in human iPSC-derived neurons

Massey, S; Ang, CS; Davidson, NM; Quigley, A; Rollo, B; Harris, AR; Kapsa, RMI; Christodoulou, J; JVan Bergen N

Author(s): Massey, S; Ang, CS; Davidson, NM; Quigley, A; Rollo, B; Harris, AR; Kapsa, RMI; Christodoulou, J; JVan Bergen N;
Details: Publication Year 2024-08-13,Volume 81,Issue #1,Page 347
Journal Title: Cellular and Molecular Immunology
Abstract: CDKL5 Deficiency Disorder (CDD) is a debilitating epileptic encephalopathy disorder affecting young children with no effective treatments. CDD is caused by pathogenic variants in Cyclin-Dependent Kinase-Like 5 (CDKL5), a protein kinase that regulates key phosphorylation events in neurons. For therapeutic intervention, it is essential to understand molecular pathways and phosphorylation targets of CDKL5. Using an unbiased phosphoproteomic approach we identified novel targets of CDKL5, including GTF2I, PPP1R35, GATAD2A and ZNF219 in human iPSC-derived neuronal cells. The phosphoserine residue in the target proteins lies in the CDKL5 consensus motif. We validated direct phosphorylation of GTF2I and PPP1R35 by CDKL5 using complementary approaches. GTF2I controls axon guidance, cell cycle and neurodevelopment by regulating expression of neuronal genes. PPP1R35 is critical for centriole elongation and cilia morphology, processes that are impaired in CDD. PPP1R35 interacts with CEP131, a known CDKL5 phospho-target. GATAD2A and ZNF219 belong to the Nucleosome Remodelling Deacetylase (NuRD) complex, which regulates neuronal activity-dependent genes and synaptic connectivity. In-depth knowledge of molecular pathways regulated by CDKL5 will allow a better understanding of druggable disease pathways to fast-track therapeutic development.
Publisher: Springer
Keywords: Humans; *Induced Pluripotent Stem Cells/metabolism/cytology; *Neurons/metabolism/cytology; *Protein Serine-Threonine Kinases/metabolism/genetics; Phosphorylation; *Epileptic Syndromes/metabolism/genetics/pathology; *Spasms, Infantile/metabolism/genetics/pathology; CDKL5 deficiency disorder; Gtf2i; Kinase; Neurodevelopmental disorder; Ppp1r35; Phosphoproteomics
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 39136782
Publisher's Version: https://doi.org/10.1007/s00018-024-05389-8
Open Access at Publisher's Site: https://doi.org/10.1007/s00018-024-05389-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s00018-024-05389-8.pdf - (6.06MB, application/pdf)

Creation Date: 2024-08-23 02:54:18

Last Modified: 2024-08-23 03:05:45