title: Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5.
abstract: Mutations in the X-linked CDKL5 (cyclin-dependent kinase-like 5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged, whereas in more mature neurons, NMDA receptor stimulation induces a protein phosphatase 1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome-dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape, and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation, and refinement.
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Paolo
authors.initials: P
authors.lastname: La Montanara
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Laura
authors.initials: L
authors.lastname: Rusconi
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Albina
authors.initials: A
authors.lastname: Locarno
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Lia
authors.initials: L
authors.lastname: Forti
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Barbiero
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Marco
authors.initials: M
authors.lastname: Tramarin
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Chetan
authors.initials: C
authors.lastname: Chandola
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kilstrup-Nielsen
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research; University of Insubria, 21052 Busto Arsizio, Italy and the San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy landsben@uninsubria.it.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D017346:Protein Serine-Threonine Kinases; C533690:CDKL5 protein, mouse; D054645:Protein Phosphatase 1; D046988:Proteasome Endopeptidase Complex
keywords: CDKL5; Dephosphorylation; Local Protein Synthesis; Neurological Disease; Neuronal Depolarization; Post-transcriptional Regulation; Protein Degradation; Protein Expression; Protein Phosphorylation; Synaptic Plasticity