CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons

• Published in: Nature cell biology Vol. 14; no. 9; pp. 911 - 923
• Main Authors: Ricciardi, Sara, Ungaro, Federica, Hambrock, Melanie, Rademacher, Nils, Stefanelli, Gilda, Brambilla, Dario, Sessa, Alessandro, Magagnotti, Cinzia, Bachi, Angela, Giarda, Elisa, Verpelli, Chiara, Kilstrup-Nielsen, Charlotte, Sala, Carlo, Kalscheuer, Vera M, Broccoli, Vania
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2012
• Subjects: Amino Acid Sequence; Animals; Biology; Cell Adhesion - genetics; Cell Adhesion - physiology; Cells, Cultured; Chlorocebus aethiops; COS Cells; Cyclin-dependent kinases; Dendritic Spines - metabolism; Dendritic Spines - pathology; Disks Large Homolog 4 Protein; Excitatory Postsynaptic Potentials - genetics; Excitatory Postsynaptic Potentials - physiology; Female; Gene mutations; Genetic aspects; Genetics; Glutamic Acid - metabolism; Health aspects; HEK293 Cells; Humans; Intellectual disabilities; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Localization; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Molecular Sequence Data; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - metabolism; Neurons - physiology; Neurosciences; Patients; Phosphorylation; Physiological aspects; Protein kinases; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rett Syndrome - pathology; Spine - metabolism; Spine - pathology; Synapses; Synapses - genetics; Synapses - metabolism; Italy
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2566

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.