The Synaptic and Neuronal Functions of the X‐Linked Intellectual Disability Protein Interleukin‐1 Receptor Accessory Protein Like 1 (IL1RAPL1)

Abstract

Since the first observation that described a patient with a mutation in IL1RAPL1 gene associated with intellectual disability in 1999, the function of IL1RAPL1 has been extensively studied by a number of laboratories. In this review, we summarize all the major data describing the synaptic and neuronal functions of IL1RAPL1 and recapitulate most of the genetic deletion identified in humans and associated to intellectual disability (ID) and autism spectrum disorders (ASD). All the data clearly demonstrate that IL1RAPL1 is a synaptic adhesion molecule localized at the postsynaptic membrane. Mutations in IL1RAPL1 gene cause either the absence of the protein or the production of a dysfunctional protein. More recently it has been demonstrated that IL1RAPL1 regulated dendrite formation and mediates the activity of IL‐1β on dendrite morphology. All these data will possibly contribute to identifying therapies for patients carrying mutations in IL1RAPL1 gene.

Splice‐dependent trans‐synaptic PTP δ– IL 1 RAPL 1 interaction regulates synapse formation and non‐ REM sleep

“…These interactions are frequently regulated by splice inserts located on the extracellular regions of LAR‐RPTPs; related molecular details have been clarified by biochemical, cell biological, and X‐ray crystallographic studies (Coles et al , ; Um et al , ; Yamagata et al , 2015a; Won et al , ; Goto‐Ito et al , ; Karki et al , ; Lin et al , ). For instance, PTPδ requires the miniexon A (meA) splice insert to interact with IL1RAPL1 (Yoshida et al , ; Yamagata et al , 2015b), a postsynaptic CAM that critically regulates synaptic and neuronal functions (Montani et al , ), whereas PTPδ requires the miniexon B (meB) to interact with Slitrks, SALM3/5, and IL‐1RAcP (Takahashi et al , ; Yoshida et al , ; Yim et al , ; Um et al , ; Li et al , ; Yamagata et al , ,b; Choi et al , ).…”

Alteration of NMDA receptor trafficking as a cellular hallmark of psychosis

“…2 ). In contrast, IL1RAPL1 knockout, a genetic model of intellectual disability in which synaptic plasticity is also impaired [ 48 ] did not alter NMDAR surface dynamics in hippocampal neurons (Fig. 3c ).…”

Synaptic Formation, Neural Circuits and Neurodevelopmental Disorders Controlled by Signaling, Translation, and Epigenetic Regulation

“…In addition to the transcriptional and translational regulation and signaling control mentioned above, membrane proteins involved in cell-cell interactions play key roles in the initiation and regulation of these neuronal differentiation processes. In this Special Issue, two membrane proteins-Interleukin-1 receptor accessory protein like 1 (IL1RAPL1) and Protocadherin-19 (PCDH19)-are used as examples to reveal how adhesion molecules are relevant to neurodevelopmental disorders (Gerosa et al, 2018;Montani et al, 2018). IL1RAPL1 is associated with intellectual disability and ASD.…”

“…Although it was originally identified as an IL‐1 receptor associated protein that mediates IL‐1 signaling (Carrie et al ., ; Born et al ., ), it was found to localize at the postsynaptic site, particularly at the hippocampus, and contribute to synaptic interactions. Il1rapl1 deficiency results in altered dendritic spine formation and dendritic arborization (Montani et al ., ), which may account for the disease mechanism of IL1RAPL1‐related neurodevelopmental disorders. PCDH19, a member of the protocadherin protein family, is considered one of the most clinically relevant genes for female epilepsy (OMIM#300088).…”