title: A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation.
abstract: BACKGROUND
  Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene mutations are associated with cognitive impairment ranging from nonsyndromic X-linked mental retardation to autism. IL1RAPL1 belongs to a novel family of Toll/IL-1 receptors, whose expression in the brain is upregulated by neuronal activity. Currently, very little is known about the function of this protein. We previously showed that IL1RAPL1 interacts with the neuronal calcium sensor NCS-1 and that it regulates voltage-gated calcium channel activity in PC12 cells.
  
  
  RESULTS
  Here we show that IL1RAPL1 is present in dendritic spine where it interacts with PSD-95, a major component of excitatory postsynaptic compartment. Using gain- and loss-of-function experiments in neurons, we demonstrated that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling c-Jun terminal kinase (JNK) activity and PSD-95 phosphorylation. Mice carrying a null mutation of the mouse Il1rapl1 gene show a reduction of both dendritic spine density and excitatory synapses in the CA1 region of the hippocampus. These structural abnormalities are associated with specific deficits in hippocampal long-term synaptic plasticity.
  
  
  CONCLUSIONS
  The interaction of IL1RAPL1 with PSD-95 discloses a novel pathophysiological mechanism of cognitive impairment associated with alterations of the JNK pathway leading to a mislocalization of PSD-95 and abnormal synaptic organization and function.
authors.affiliation: Department of Genetics and Development, Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, 75014 Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Pavlowsky
authors.forename: Antonella
authors.initials: A
authors.lastname: Gianfelice
authors.forename: Marta
authors.initials: M
authors.lastname: Pallotto
authors.forename: Alice
authors.initials: A
authors.lastname: Zanchi
authors.forename: Hugo
authors.initials: H
authors.lastname: Vara
authors.forename: Malik
authors.initials: M
authors.lastname: Khelfaoui
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.forename: Xavier
authors.initials: X
authors.lastname: Rezai
authors.forename: Silvia
authors.initials: S
authors.lastname: Bassani
authors.forename: Dario
authors.initials: D
authors.lastname: Brambilla
authors.forename: Jiri
authors.initials: J
authors.lastname: Kumpost
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Blahos
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Roux
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.forename: Maurizio
authors.initials: M
authors.lastname: Giustetto
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
mesh_terms: D000818:Animals; D003071:Cognition; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; C521481:IL1RAPL1 protein, rat; D053577:Interleukin-1 Receptor Accessory Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins