title: 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.affiliation: Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ricciardi
authors.forename: Federica
authors.initials: F
authors.lastname: Ungaro
authors.forename: Melanie
authors.initials: M
authors.lastname: Hambrock
authors.forename: Nils
authors.initials: N
authors.lastname: Rademacher
authors.forename: Gilda
authors.initials: G
authors.lastname: Stefanelli
authors.forename: Dario
authors.initials: D
authors.lastname: Brambilla
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sessa
authors.forename: Cinzia
authors.initials: C
authors.lastname: Magagnotti
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Elisa
authors.initials: E
authors.lastname: Giarda
authors.forename: Chiara
authors.initials: C
authors.lastname: Verpelli
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kilstrup-Nielsen
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013131:Spine / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; C480698:LRRC4C protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018698:Glutamic Acid; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human