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Molecular Autism
Published in: Molecular Autism 1/2015

Open Access 01-12-2015 | Research

The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis

Authors: Eriko Fujita-Jimbo, Yuko Tanabe, Zhiling Yu, Karin Kojima, Masato Mori, Hong Li, Sadahiko Iwamoto, Takanori Yamagata, Mariko Y Momoi, Takashi Momoi

Published in: Molecular Autism | Issue 1/2015

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Abstract

Background

Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain.

Methods

We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons.

Results

The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons.

Conclusions

GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex.
Appendix
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Metadata
Title
The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis
Authors
Eriko Fujita-Jimbo
Yuko Tanabe
Zhiling Yu
Karin Kojima
Masato Mori
Hong Li
Sadahiko Iwamoto
Takanori Yamagata
Mariko Y Momoi
Takashi Momoi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2015
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-015-0012-5

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