Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.
Pubmed ID: 22922712 RIS Download
Mesh terms: Amino Acid Sequence | Animals | COS Cells | Cell Adhesion | Cells, Cultured | Cercopithecus aethiops | Dendritic Spines | Excitatory Postsynaptic Potentials | Female | Glutamic Acid | HEK293 Cells | Humans | Intracellular Signaling Peptides and Proteins | Membrane Proteins | Mice | Molecular Sequence Data | Mutation | Nerve Tissue Proteins | Neurons | Phosphorylation | Protein-Serine-Threonine Kinases | Receptors, Cell Surface | Rett Syndrome | Spine | Synapses
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