CDKL5 Ensures Excitatory Synapse Stability by Reinforcing NGL-1-PSD95 Interaction in the Postsynaptic Compartment and is Impaired in Patient IPSC-derived Neurons

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2012 Aug 28

PMID 22922712

Citations 127

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

Affiliations

Soon will be listed here.

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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