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.
Highlights
Associated with intellectual disability, CDKL5 functions and regulation are poorly understood
Neuronal Activation Triggers a Rapid, Protein Synthesis-dependent Increase in CDKL5 Levels—As described in the introduction, CDKL5 might play a pivotal role in converting the effects of transient neuronal stimuli into changes in the molecular pathways that are important for the brain to process information
The response of CDKL5 to neuronal depolarization was analyzed by using a specific antibody [6], and as shown in Fig. 1 (B and C), CDKL5 levels significantly increased after 5 min of treatment; as expected, no increment could be detected in the protein levels of ERK1/2 and c-Fos (Fig. 1C and data not shown)
Summary
Paolo La Montanara‡, Laura Rusconi‡, Albina Locarno‡, Lia Forti‡, Isabella Barbiero‡, Marco Tramarin‡, Chetan Chandola‡, Charlotte Kilstrup-Nielsen‡1, and Nicoletta Landsberger‡§1,2 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
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