title: HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder.
abstract: 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.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuchs
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Rocchina
authors.initials: R
authors.lastname: Viggiano
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: De Franceschi
authors.affiliation: Department of Pharmacy and Biotechnology, and CIRI Health Sciences and Technologies.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valli
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Paulina
authors.initials: P
authors.lastname: Jedynak
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität, Düsseldorf, Germany.
authors.forename: Finn K
authors.initials: FK
authors.lastname: Hansen
authors.affiliation: Department of Pharmacy and Biotechnology, and CIRI Health Sciences and Technologies.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.affiliation: Department of Medical and Clinical Sciences, University of Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy elisabetta.ciani@unibo.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D000073376:Epileptic Syndromes; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D064326:MEF2 Transcription Factors / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D058953:Neural Stem Cells / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015518:Rett Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013036:Spasms, Infantile / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D017346:Protein Serine-Threonine Kinases; C533690:CDKL5 protein, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases