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.
Synaptic synthesis, dephosphorylation, and degradation: A novel paradigm for an activity-dependent neuronal control of CDKL5 / P. La Montanara, L. Rusconi, A. Locarno, L. Forti, I. Barbiero, M. Tramarin, C. Chandola, C. Kilstrup-Nielsen, N. Landsberger. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 290:7(2015), pp. 4512-4527.
|Titolo:||Synaptic synthesis, dephosphorylation, and degradation: A novel paradigm for an activity-dependent neuronal control of CDKL5|
LANDSBERGER, NICOLETTA (Ultimo) (Corresponding)
|Parole Chiave:||BDNF transcription; protein-synthesis; rett-syndrome; CDKL5; kinase; mechanisms; phosphorylation; expression; plasticity; receptors|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1074/jbc.M114.589762|
|Appare nelle tipologie:||01 - Articolo su periodico|