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Cyclin-dependent kinase-like 5  (CDKL5)  is a Ser/Thr protein kinase predominantly expressed in the brain. Mutations of the  CDKL5  gene lead to  CDKL5  disorder, a neurodevelopmental pathology that shares several features with Rett Syndrome and is characterized by severe intellectual disability. The phosphorylation targets of  CDKL5  are largely unknown, which hampers the discovery of therapeutic strategies for improving the neurological phenotype due to  CDKL5  mutations. Here, we show that the histone deacetylase 4 (HDAC4) is a direct phosphorylation target of  CDKL5  and that  CDKL5 -dependent phosphorylation promotes HDAC4 cytoplasmic retention. Nuclear HDAC4 binds to chromatin as well as to MEF2A transcription factor, leading to histone deacetylation and altered neuronal gene expression. By using a  Cdkl5  knockout  (Cdkl5 -/Y)  mouse model, we found that hypophosphorylated HDAC4 translocates to the nucleus of neural precursor cells, thereby reducing histone 3 acetylation. This effect was reverted by re-expression of  CDKL5  or by inhibition of HDAC4 activity through the HDAC4 inhibitor LMK235. In  Cdkl5  -/Y mice treated with LMK235, defective survival and maturation of neuronal precursor cells and hippocampus-dependent memory were fully normalized. These results demonstrate a critical role of HDAC4 in the neurodevelopmental alterations due to  CDKL5  mutations and suggest the possibility of HDAC4-targeted pharmacological interventions.

HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder