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.

CONCLUSION:

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: Alice Pavlowsky, Antonella Gianfelice, Marta Pallotto, Alice Zanchi, Hugo Vara, Malik Khelfaoui, Pamela Valnegri, Xavier Rezai, Silvia Bassani, Dario Brambilla, Jiri Kumpost, Jaroslav Blahos, Michel J Roux, Yann Humeau, Jamel Chelly, Maria Passafaro, Maurizio Giustetto, Pierre Billuart, Carlo Sala
• Journal: Current biology : CB (Curr Biol) Vol. 20 Issue 2 Pg. 103-15 (Jan 26 2010) ISSN: 1879-0445 [Electronic] England
• PMID: 20096586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Disks Large Homolog 4 Protein
• Dlg4 protein, rat
• IL1RAPL1 protein, rat
• Interleukin-1 Receptor Accessory Protein
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins

Topics

• Animals
• Cognition
• Disks Large Homolog 4 Protein
• Hippocampus (cytology, metabolism)
• Interleukin-1 Receptor Accessory Protein (genetics, physiology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Membrane Proteins (metabolism)
• Mice
• Mutation
• PC12 Cells
• Phosphorylation
• Rats
• Signal Transduction
• Synapses (metabolism)