Astroglial dysfunction in models of CDKL5 deficiency disorder
4 affiliations
- 1Gene Therapy, Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom
- 2Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- 3Department of Neurosurgery, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
- 4Department of Paediatric Neurology, The Portland Hospital, HCA Healthcare, London, United Kingdom
Abstract
CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy typically caused by loss of function variants in the gene encoding the X-linked serine–threonine kinase CDKL5. CDKL5 is highly expressed in the brain during development, and key neuronal functions of the kinase include cytoskeletal organisation and synaptic stability. However, at present, little is known about the function of astroglia in CDD. Given the importance of these cells in synaptic development and homeostasis, as well as dysfunction in other epileptic diseases, it was hypothesised that astrocytes may contribute to CDD pathology. Induced pluripotent stem cells harbouring a CDKL5 loss-of-function mutation (and isogenic controls) were derived from CDD patient fibroblasts and differentiated into astrocytes (iAstros). Analysis of iAstros revealed transcriptomic, proteomic and functional dysregulation in CDKL5-mutant iAstros relating to water transport and immunological function, including a diminished response to TNFα stimulation. Moreover, iAstros showed increased branching and reduced phosphorylation of the known CDKL5 target end-binding protein 2 (EB2) - indicative of disrupted cytoskeletal regulation in a manner similar to CDKL5-null neurons. Finally, we report proof-of-concept of novel in vitro models of CDD. CDKL5 was knocked down in adult and foetal human organotypic brain slices through transduction with an AAV encoding a novel CDKL5 shRNA. Slices transduced with the CDKL5 shRNA displayed a trending increase in spontaneous network activity compared to those transduced with a scrambled control, demonstrating the functionality of this model. Importantly, interrogation of these models revealed dysregulation of key astrocytic proteins congruent with the human glial stem cell model. Consequently, this study describes the generation of novel human models of CDD and initial findings of astrocytic dysfunction – paving the way for novel discovery and therapeutic intervention.
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BibTeX
@article{pickering2026astroglial,
title = {{Astroglial dysfunction in models of CDKL5 deficiency disorder}},
author = {Ceri Pickering and Adriana Bakoulina and Faye McLeod and Angeliki Pantziarou and Antriksh A. Goyal and Zhi Yi Alicia Seet and Alishba Saleemi and Yimiao Wu and Gavin John Clowry and Christopher J. A. Cowie and Maria Kinali and Nicholas D. Mazarakis},
journal = {Frontiers in Cellular Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fncel.2026.1934251},
url = {https://doi.org/10.3389/fncel.2026.1934251},
note = {CC BY},
}
RIS
TY - JOUR
TI - Astroglial dysfunction in models of CDKL5 deficiency disorder
AU - Ceri Pickering
AU - Adriana Bakoulina
AU - Faye McLeod
AU - Angeliki Pantziarou
AU - Antriksh A. Goyal
AU - Zhi Yi Alicia Seet
AU - Alishba Saleemi
AU - Yimiao Wu
AU - Gavin John Clowry
AU - Christopher J. A. Cowie
AU - Maria Kinali
AU - Nicholas D. Mazarakis
PY - 2026
DA - 2026/10/30
JO - Frontiers in Cellular Neuroscience
DO - 10.3389/fncel.2026.1934251
UR - https://doi.org/10.3389/fncel.2026.1934251
AB - CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy typically caused by loss of function variants in the gene encoding the X-linked serine–threonine kinase CDKL5. CDKL5 is highly expressed in the brain during development, and key neuronal functions of the kinase include cytoskeletal organisation and synaptic stability. However, at present, little is known about the function of astroglia in CDD. Given the importance of these cells in synaptic development and homeostasis, as well as dysfunction in other epileptic diseases, it was hypothesised that astrocytes may contribute to CDD pathology. Induced pluripotent stem cells harbouring a CDKL5 loss-of-function mutation (and isogenic controls) were derived from CDD patient fibroblasts and differentiated into astrocytes (iAstros). Analysis of iAstros revealed transcriptomic, proteomic and functional dysregulation in CDKL5-mutant iAstros relating to water transport and immunological function, including a diminished response to TNFα stimulation. Moreover, iAstros showed increased branching and reduced phosphorylation of the known CDKL5 target end-binding protein 2 (EB2) - indicative of disrupted cytoskeletal regulation in a manner similar to CDKL5-null neurons. Finally, we report proof-of-concept of novel in vitro models of CDD. CDKL5 was knocked down in adult and foetal human organotypic brain slices through transduction with an AAV encoding a novel CDKL5 shRNA. Slices transduced with the CDKL5 shRNA displayed a trending increase in spontaneous network activity compared to those transduced with a scrambled control, demonstrating the functionality of this model. Importantly, interrogation of these models revealed dysregulation of key astrocytic proteins congruent with the human glial stem cell model. Consequently, this study describes the generation of novel human models of CDD and initial findings of astrocytic dysfunction – paving the way for novel discovery and therapeutic intervention.
SN - 1662-5102
ER -