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

Abstract

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.

• Authors: Sara Ricciardi, Federica Ungaro, Melanie Hambrock, Nils Rademacher, Gilda Stefanelli, Dario Brambilla, Alessandro Sessa, Cinzia Magagnotti, Angela Bachi, Elisa Giarda, Chiara Verpelli, Charlotte Kilstrup-Nielsen, Carlo Sala, Vera M Kalscheuer, Vania Broccoli
• Journal: Nature cell biology (Nat Cell Biol) Vol. 14 Issue 9 Pg. 911-23 (Sep 2012) ISSN: 1476-4679 [Electronic] England
• PMID: 22922712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DLG4 protein, human
• Disks Large Homolog 4 Protein
• Intracellular Signaling Peptides and Proteins
• LRRC4C protein, human
• Membrane Proteins
• Nerve Tissue Proteins
• Receptors, Cell Surface
• Glutamic Acid
• Protein Serine-Threonine Kinases
• CDKL5 protein, human

Topics

• Amino Acid Sequence
• Animals
• COS Cells
• Cell Adhesion (genetics, physiology)
• Cells, Cultured
• Chlorocebus aethiops
• Dendritic Spines (metabolism, pathology)
• Disks Large Homolog 4 Protein
• Excitatory Postsynaptic Potentials (genetics, physiology)
• Female
• Glutamic Acid (metabolism)
• HEK293 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Molecular Sequence Data
• Mutation
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (metabolism, physiology)
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Rett Syndrome (genetics, metabolism, pathology)
• Spine (metabolism, pathology)
• Synapses (genetics, metabolism)