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

Ricciardi, S., Ungaro, F., Hambrock, M., Rademacher, N., Stefanelli, G., Brambilla, D., et al. (2012). CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nature Cell Biology, 14(9), 911-923. doi:10.1038/ncb2566.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-EC80-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-EC81-C
Genre: Journal Article

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 Creators:
Ricciardi, S., Author
Ungaro, F., Author
Hambrock, M.1, Author              
Rademacher, N.2, Author              
Stefanelli, G., Author
Brambilla, D., Author
Sessa, A., Author
Magagnotti, C., Author
Bachi, A., Author
Giarda, E., Author
Verpelli, C., Author
Kilstrup-Nielsen, C., Author
Sala, C., Author
Kalscheuer, V. M.1, Author              
Broccoli, V., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479642              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1433549              

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Free keywords: Amino Acid Sequence Animals COS Cells Cell Adhesion/genetics/physiology Cells, Cultured Cercopithecus aethiops Dendritic Spines/metabolism/pathology 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
 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.

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Language(s): eng - English
 Dates: 2012-08-262012-09
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/ncb2566
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Macmillan Magazines Ltd.
Pages: - Volume / Issue: 14 (9) Sequence Number: - Start / End Page: 911 - 923 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310