Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics.

Daji Guo,Xiaoman Yang,Lei Shi

doi:10.3390/cells9040835

Daji Guo, Xiaoman Yang + Show 1 more

Open Access

https://doi.org/10.3390/cells9040835

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Journal: Cells	Publication Date: Mar 31, 2020
Citations: 40	License type: CC BY 4.0

Affiliation: Jinan University, University of Hong Kong

Abstract

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two core symptoms: (1) impaired social interaction and communication, and (2) repetitive or restricted interest and behaviors
By examining the overlap of RhoGEF genes and Simons foundation autism research initiative (SFARI) Gene, we find the following seven RHOGEFs as ASD-risk genes: ARHGEF9, TRIO, DOCK8, PREX1, ARHGEF10, DOCK1, and DOCK4 (Table 1)
By overlapping 57 GTPase-activating proteins (GAPs) domain-containing RhoGAP genes [26] with SFARI Gene, we find eight RHOGAPs as ASD-risk genes: MYO9B, Oligophrenin 1 (OPHN1), ARHGAP5, ARHGAP11B, ARHGAP32, SRGAP3, and OCRL (Table 1)

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two core symptoms: (1) impaired social interaction and communication, and (2) repetitive or restricted interest and behaviors. Gene [14] and more than 1000 genes have been listed in AutDB [15] Among these ASD susceptibility genes, many converge on synapse regulation such as the regulation of development and maturation of synaptic contacts and synaptic transmission [16,17,18]. Rho GTPase activity is regulated by two different kinds of regulatory protein: guanine nucleotide nucleotide exchange exchange factors factors (GEFs),. We find that all these genes encode regulatory or directly participate in Rho GTPase signaling. Approaches that are capable of correcting abnormalities caused by dysfunctions of these Rho therapeutic approaches that are capable ofthe correcting the abnormalities caused by dysfunctions of GTPase regulators and effectors are discussed.

Rho Family GTPases and ASD

RhoGEF Family and ASD

Result

RhoGAP Family and ASD

Rho GTPase Effectors and ASD

Conclusions

Methods