ArticleMolecular psychiatry2024
Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain.
Article in Molecular psychiatry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates.bioRxiv : the preprint server for biology · 2026Article
- The CDKL5 kinase undergoes liquid-liquid phase separation driven by a serine-rich C-terminal region.Life science alliance · 2026Article
- High-Definition Brain Network (HDBN) Delineation of CDKL5 Deficiency Disorder (CDD) in Genetically Engineered Mice.Biomolecules · 2026Article
- CDKL5 modulates the plasticity of excitatory synapses via liquid-liquid phase separation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Altered Short Non-Coding RNA Landscape in the Hippocampus of a Mouse Model of CDKL5 Deficiency Disorder.Biomolecules · 2025Article
- Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons.Neurobiology of disease · 2025Article
- Safety and efficacy of Igk-TATk-CDKL5 gene therapy in mosaic CDKL5 deficiency.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- CDKL5 Deficiency Disorder: Revealing the Molecular Mechanism of Pathogenic Variants.International journal of molecular sciences · 2025Article
- Adult-Onset Deletion of CDKL5 in Forebrain Glutamatergic Neurons Impairs Synaptic Integrity and Behavior in Mice.International journal of molecular sciences · 2025Article
- De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms.American journal of human genetics · 2025Article
- Independent genetic strategies define the scope and limits of CDKL5 deficiency disorder reversal.Cell reports. Medicine · 2025Article
- A cross-correction gene therapy approach for CDKL5 deficiency disorder improves the pathological phenotype of CDD patient-derived cortical organoids.Frontiers in bioengineering and biotechnology · 2025Article
- A phylogenetic analysis of the CDKL protein family unravels its evolutionary history and supports theFrontiers in cell and developmental biology · 2025Article
- Bacterial Production of CDKL5 Catalytic Domain: Insights in Aggregation, Internal Translation and Phosphorylation Patterns.International journal of molecular sciences · 2024Article
- Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2.ACS medicinal chemistry letters · 2024Article
- Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2.bioRxiv : the preprint server for biology · 2024Article
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5 authors.
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Abstract
CDKL5 is a brain-enriched serine/threonine kinase, associated with a profound developmental and epileptic encephalopathy called CDKL5 deficiency disorder (CDD). To design targeted therapies for CDD, it is essential to determine where CDKL5 is expressed and is active in the brain and test if compensatory mechanisms exist at cellular level. We generated conditional Cdkl5 knockout mice in excitatory neurons, inhibitory neurons and astrocytes. To assess CDKL5 activity, we utilized a phosphospecific antibody for phosphorylated EB2, a well-known substrate of CDKL5. We found that CDKL5 and EB2 pS222 were prominent in excitatory and inhibitory neurons but were not detected in astrocytes. We observed that approximately 15-20% of EB2 pS222 remained in Cdkl5 knockout brains and primary neurons. Surprisingly, the remaining phosphorylation was modulated by NMDA and PP1/PP2A in neuronal CDKL5 knockout cultures, indicating the presence of a compensating kinase. Using a screen of candidate kinases with highest homology to the CDKL5 kinase domain, we found that CDKL2 and ICK can phosphorylate EB2 S222 in HEK293T cells and in primary neurons. We then generated Cdkl5/Cdkl2 dual knockout mice to directly test if CDKL2 phosphorylates EB2 in vivo and found that CDKL2 phosphorylates CDKL5 substrates in the brain. This study is the first indication that CDKL2 could potentially replace CDKL5 functions in the brain, alluding to novel therapeutic possibilities.
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